Biaryl ligands, methods of making biarlyl ligands, and methods of use thereof

ABSTRACT

Embodiments of the present disclosure provide for biaryl ligands (also referred to herein as “biaryl compound”), biaryl complexes, methods of making biaryl compounds, methods of making single enantiomers of these biaryl compounds, methods of use (e.g., catalysis), and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/927,505 entitled “BIARYL LIGANDS, METHODS OFMAKING BIARYL LIGANDS, AND METHODS OF USE THEREOF,” filed on Mar. 21,2018, which is a continuation application of U.S. patent applicationSer. No. 15/021,053 entitled “BIARYL LIGANDS, METHODS OF MAKING BIARYLLIGANDS, AND METHODS OF USE THEREOF,” filed on Mar. 10, 2016 and issuedon Jun. 12, 2018 as U.S. Pat. No. 9,994,599.

U.S. patent application Ser. No. 15/021,053 (issued as U.S. Pat. No.9,994,599) is the 35 U.S.C. § 371 national stage application of PCTApplication No. PCT/US2014/055356, filed Sep. 12, 2014. PCT ApplicationNo. PCT/US2014/055356 claims priority to U.S. Provisional PatentApplication No. 61/877,505 entitled “BIARYL LIGANDS, METHODS OF MAKINGBIARYL LIGANDS, AND METHODS OF USE THEREOF,” filed on Sep. 13, 2013, andthe PCT Application also claims priority to U.S. Provisional PatentApplication No. 61/881,480 entitled “BIARYL LIGANDS, METHODS OF MAKINGBIARYL LIGANDS, AND METHODS OF USE THEREOF,” filed on Sep. 24, 2013.

All of the aforementioned patents or patent applications are entirelyincorporated herein by reference.

BACKGROUND

The development of new chiral ligands is essential for enantioselectivecatalysis and continues to be an important area at the forefront oforganic synthesis. Of particular importance are new ligands thatintroduce fundamental changes in the chiral backbone and/or unique modesof coordination.

SUMMARY

Embodiments of the present disclosure provide for biaryl ligands (alsoreferred to herein as “biaryl compound”), biaryl complexes, methods ofmaking biaryl compounds, methods of making single enantiomers of thesebiaryl compounds, methods of use (e.g., catalysis), and the like.

One exemplary composition, among others, includes: a single biarylenantiomer of the following structure:

wherein the A ring is selected from a benzenoid, a 5 or 6-memberedheteroaromatic ring, or an aryl or heteroaryl fused-ring, system,wherein each of the R₅ groups is independently selected from: hydrogen,a halogen group, a cyclic or linear, alkyl group, an aryl group, a —ORgroup, a —SR group, a —SiR₃ group, a NR₂ cyclic or linear group, whereinR is selected from: hydrogen, a cyclic or linear, alkyl group, or anaryl group, wherein n is 1 to 5, wherein X is CR₂ or SO₂; wherein the Bring is selected from a 5-member or fused-ring heteroaromatic system;and wherein the C ring is selected from a benzenoid, a 5 or 6-memberedheteroaromatic ring, or an aryl or heteroaryl fused-ring, system,wherein each of the R₃ groups is independently selected from: hydrogen,a cyclic or linear, alkyl group, an alkoxide, a phenoxide, an arylgroup, or a substituted amine, wherein each R group is independentlyselected.

One exemplary composition, among others, includes: a single biarylenantiomer of the following structure:

wherein each R₆ and R₇ group is independently selected from: hydrogen, acyclic or linear, alkyl group, an aryl group, wherein when X is SO₂, R₆and R₇ are not present; wherein each Q1, Q2, Q3, Q4, and Q5 areindependently selected from C, N, O, or S, wherein one of Q1, Q2, Q3,Q4, and Q5 is selected from N, O, or S, and the other of Q1, Q2, Q3, Q4,and Q5 are selected from C, N, O, or S, wherein R₁ and R₂ areindependently selected from: hydrogen, a halogen group, a cyclic orlinear, alkyl group, an aryl group, a —OR group, a —SR group, a —SiR₃group, a NR₂ cyclic or linear group, wherein R is selected from:hydrogen, a cyclic or linear, alkyl group, or an aryl group; and whereineach of the R₄ groups is selected from: hydrogen, a halogen group, acyclic or linear, alkyl group, an aryl group, a —OR group, a —SR group,a —SiR₃ group, a NR₂ cyclic or linear group, wherein R is selected from:hydrogen, a cyclic or linear, alkyl group, alkoxides, phenoxides, arylgroups, or substituted amines, wherein m is 1 to 5.

One exemplary composition, among others, includes: a single biarylenantiomer of the following structure:

One exemplary method of making a biaryl compound, among others,includes:

wherein the biaryl product has the following structure:

as described herein.

One exemplary method of forming a compound, among others, includes:

One exemplary method of forming a compound, among others, includes:

One exemplary method of forming a compound, among others, includes:using a biaryl compound as a catalyst in a reaction selected from one ofthe following: an enantioselective transformation, an enantioselectiveA³ coupling, an alkyne addition asymmetric allylic alkylation, and anaddition to a aliphatic or an aromatic aldehyde.

One exemplary method, among others, includes:

wherein R is shown in Table 1, Example 2, and compound 7 is

One exemplary method, among others, includes:

wherein compound 7 is

and wherein R is selected from SiMe₃ and Ph.

One exemplary method, among others, includes:

wherein compound rac-7 is

One exemplary method, among others, includes:

wherein compound 7 is

One exemplary composition, among others, includes: a complex having thefollowing structure:

wherein MET is a metal selected from the group consisting of, but notlimited to: a transition metal, Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, Pt, Cu,and Au, wherein z is 1 to 3, wherein L refers to a ligand selected fromthe group consisting of: amide, phenolate, thiolate, halogen,carboxylate, acetylacetonate, phosphine, phosphite, and phosphoramidite,wherein u is 1 to 5, wherein MET is bonded to a N, S, or O group in theB ring.

Another exemplary composition, among others, includes: a complex havingthe following structure:

Other compositions, methods, features, and advantages of this disclosurewill be or become apparent to one with skill in the art upon examinationof the following drawings and detailed description. It is intended thatall such additional systems, methods, features, and advantages beincluded within this description, be within the scope of thisdisclosure, and be protected by the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure will be more readilyappreciated upon review of the detailed description of its variousembodiments, described below, when taken in conjunction with theaccompanying drawings.

FIG. 1.1 illustrates an ortho-substitution of a compound.

FIG. 1.2 illustrates the bond angle effect.

FIG. 1.3 illustrates QUINAP derivatives.

FIG. 1.4 illustrates the bite angle effect.

FIG. 1.5 illustrates strategies for increasing barrier height.

FIG. 1.6 illustrates using n-stacking to stabilize the ground state.

FIG. 1.7 illustrates ¹H NMR spectra of 11 and 10 at 25° C. in CDCl₃.

FIG. 1.8 illustrates the coalescence data for 11 and 10.

FIG. 1.9 illustrates X-ray structure of 10.

FIG. 1.10 illustrates the comparison of pyrrole and indole biaryls.

FIG. 1.11 illustrates the crystal structure of free ligand, 2perspectives.

FIG. 1.12 illustrates the crystal structures of 20 and BINAP inPd(II)-complexes (additional ligands omitted for clarity).

FIG. 1.13 illustrates sites of modification.

FIG. 2.1 illustrates that the racemic ligand 1 can ultimately be reactedto form 4 in 98% ee.

FIG. 3.1 illustrates the configurationally unstable ligand 4.

FIG. 3.2 illustrate stabilization of the chiral conformation in 7.

FIG. 3.3 illustrates synthesis of racemic ligand 7.

FIG. 3.4 illustrates deracemization of ligand 7.

FIG. 3.5 illustrates X-Ray crystal structure showing π-stacking.

FIG. 3.6 illustrates alkyne addition with 19.

FIG. 4.1 illustrates transformation of the products 4 a, 4 i, and 4 j togalipinine, angustureine, and cuspareine.

FIG. 4.2 illustrates palladium-catalyzed allylic alkylation.

FIG. 4.3 embodiments of ligands.

FIG. 5.1 illustrates axially chiral P,N-ligands.

FIG. 5.2 illustrates P,N-ligands containing a 5-membered heteroaromaticbiaryl.

FIG. 5.3 illustrates geometrical distinctions between 6 and 5-memberedrings in a heteroaromatic biaryls.

FIG. 5.4 illustrates using arene-arene interactions to stabilize thechiral conformation in biaryls.

FIG. 5.5 illustrates ¹H NMR spectra (300 MHz in CDCl₃) of 13 and 14.

FIG. 5.6 illustrates the temperature-dependent NMR signals (300 MHz inCDCl₃) of the methylene protons in 13 and 14.

FIG. 5.7 illustrates the X-Ray crystal structure of 14.

FIG. 5.8 illustrates the variation of the naphthalene ring.

FIG. 5.9 illustrates the variation of the benzyl group.

FIG. 5.10 illustrates the complexation of racemic ligand rac-5 withpalladacycle 24 and equilibration to a single diastereomer 25.

FIG. 5.11 illustrates the complexation with palladacycle 27.

FIG. 5.12 illustrates ortep plot of 2526 cocrystal (25 right, 26 left)with hydrogen atoms and PF6-counterions omitted for clarity.

FIG. 5.13 illustrates conformation analysis of diastereomers 25 and 26(counterions omitted and phenyl groups displayed in wireframe forclarity).

FIG. 5.14 illustrates comparison between X-ray crystal structures ofStackPhos 5, 25, and 29 (chiral auxiliary, hydrogen atoms, andcounterions omitted for clarity).

FIG. 5.15 illustrates A³-coupling employing ligand 5.

FIG. 5.16A illustrates ortep plot of QUINAP/CuBr complex 33. FIG. 5.16Billustrates ortep plot of dimer 34. FIG. 5.16C illustrates the proposedformation of complex 34 (phenyl groups shown in wireframe for clarity).

DETAILED DESCRIPTION

Before the present disclosure is described in greater detail, it is tobe understood that this disclosure is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present disclosure will be limited onlyby the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit (unlessthe context clearly dictates otherwise), between the upper and lowerlimit of that range, and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the disclosure, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure, the preferredmethods and materials are now described.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure. Any recited method can be carried out in the order of eventsrecited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwiseindicated, techniques of chemistry, catalysis, and the like, which arewithin the skill of the art. Such techniques are explained fully in theliterature.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how toperform the methods and use the compositions and compounds disclosed andclaimed herein. Efforts have been made to ensure accuracy with respectto numbers (e.g., amounts, temperature, etc.), but some errors anddeviations should be accounted for. Unless indicated otherwise, partsare parts by weight, temperature is in ° C., and pressure is inatmosphere. Standard temperature and pressure are defined as 25° C. and1 atmosphere.

Before the embodiments of the present disclosure are described indetail, it is to be understood that, unless otherwise indicated, thepresent disclosure is not limited to particular materials, reagents,reaction materials, manufacturing processes, or the like, as such canvary. It is also to be understood that the terminology used herein isfor purposes of describing particular embodiments only, and is notintended to be limiting. It is also possible in the present disclosurethat steps can be executed in different sequence where this is logicallypossible.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a support” includes a plurality of supports. In thisspecification and in the claims that follow, reference will be made to anumber of terms that shall be defined to have the following meaningsunless a contrary intention is apparent.

Definitions

The term “substituted” refers to any one or more hydrogens on thedesignated atom that can be replaced with a selection from the indicatedgroup, provided that the designated atom's normal valence is notexceeded, and that the substitution results in a stable compound. Theterm “substituted,” as in “substituted alkyl”, “substituted aryl,”“substituted heteroaryl”, and the like means, unless defined otherwiseherein, at least that the substituted group can contain in place of oneor more hydrogens a group such as alkyl, hydroxy, amino, halo,trifluoromethyl, cyano, —NH(alkyl), —N(alkyl)₂, lower alkoxy, loweralkylthio, or carboxy, and thus embraces the terms haloalkyl, alkoxy,fluorobenzyl, and the sulfur and phosphorous containing substitutionsreferred to below. In an embodiment, “substituted” refer to at least thesubstituted group can contain in place of one or more hydrogens a groupsuch as halo or C1 to C3 alkyl group.

As used herein, “alkyl” or “alkyl group” refers to a saturated aliphatichydrocarbon radical which can be straight or branched, having 1 to 20carbon atoms, wherein the stated range of carbon atoms includes eachintervening integer individually, as well as sub-ranges. Unless statedotherwise, “alkyl” or “alkyl group” includes substituted andunsubstituted alkyls. Examples of alkyl include, but are not limited tomethyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,and s-pentyl. The term “lower alkyl” means an alkyl group having lessthan 10 carbon atoms.

As used herein, “halo”, “halogen”, or “halogen radical” refers to afluorine, chlorine, bromine, and iodine, and radicals thereof. Further,when used in compound words, such as “haloalkyl” or “haloalkenyl”,“halo” refers to an alkyl or alkenyl radical in which one or morehydrogens are substituted by halogen radicals. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl.

The term “cycloalkyl” refers to a non-aromatic mono- or multicyclic ringsystem of about 3 to about 10 carbon atoms, preferably of about 5 toabout 10 carbon atoms. Preferred ring sizes of rings of the ring systeminclude about 5 to about 6 ring atoms. Unless stated otherwise,“cycloalkyl” includes substituted and unsubstituted cycloalkyls.Exemplary monocyclic cycloalkyl include cyclopentyl, cyclohexyl,cycloheptyl, and the like. Exemplary multicyclic cycloalkyl include1-decalin, norbomyl, adamant-(1- or 2-)yl, and the like.

The term “aryl” as used herein, refers to an aromatic monocyclic ormulticyclic ring system (fused rings). Unless stated otherwise, “aryl”includes substituted and unsubstituted aryls. Exemplary aryl groupsinclude phenyl or naphthyl, or phenyl substituted or naphthylsubstituted.

The term “heteroaryl” is used herein to denote an aromatic ring or fusedring structure of carbon atoms with one or more non-carbon atoms, suchas oxygen, nitrogen, and sulfur, in the ring or in one or more of therings in fused ring structures. Unless stated otherwise, “heteroaryl”includes substituted and unsubstituted heteroaryls. Examples arefuranyl, pyranyl, thienyl, imidazyl, pyrrolyl, pyridyl, pyrazolyl,pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalyl, andquinazolinyl. Preferred examples are furanyl, imidazyl, pyranyl,pyrrolyl, and pyridyl.

The term “benzenoid” is used herein to denote a substituted benzenering. Unless stated otherwise, “benzenoid” includes substituted andunsubstituted benzenoids.

The term “alkoxide” is used herein to denote a conjugate base of analcohol that includes an alkyl group.

The term “phenoixde” is used herein to denote a conjugate base of analcohol that includes a derivative of benzene.

DISCUSSION

Embodiments of the present disclosure provide for biaryl ligands (alsoreferred to herein as “biaryl compound”), biaryl complexes, methods ofmaking biaryl compounds, methods of making single enantiomers of thesebiaryl compounds, methods of use (e.g., catalysis), and the like.Embodiments of the present disclosure are advantageous over otherbiaryls that are commercially available since those of the presentdisclosure can be readily prepared and tuned, which increases theireffectiveness and reducing costs.

Embodiments of the biaryl compound are designed to lower their groundstate energy, rendering them chiral. Use of ground state stabilizationto render biaryls atropisomeric is previously unknown. In an embodiment,n-stacking (e.g., part or whole of the A ring with part of whole of theC ring) is used to increase the barrier to rotation, which allows highlyversatile 5-membered heterocyclic aromatics to be formed. Embodimentscan be produced in high enantiomeric excess and they impart highenantioselectivity in asymmetric reactions. Embodiments of these biarylcompounds can be used in asymmetric catalysis. In particular,embodiments of the biaryl compounds disclosed herein can be used inenantioselective transformations such as those described herein, but notlimited to, enantioselective A³-coupling, alkyne addition reactions,asymmetric allylic alkylation, and addition to aliphatic and aromaticaldehydes. Additional details are provided herein and in the Examples.

In an embodiment, the single biaryl enantiomer can have the followingstructure (or shown bonded to a metal):

Although each ring (e.g., ring A, B, and C) and R group (e.g., R₁ to R₇,some of which are not shown above, but in other embodiments) isdescribed separately herein and list several possible groups, anycombination of the rings and the corresponding groups described and/orthe R groups can be combined to form a plurality of distinct compounds,each of which is intended to be covered by the description providedherein. Each and every possible individual combination is not explicitlydisclosed but is intended to be disclosed. MET refers to a metal such asa transition metal, Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, Pt, Cu, Au, or thelike, where z can be 1 to 3. L refers to a ligand (e.g., amide,phenolate, thiolate, halogen, carboxylate, acetylacetonate, phosphine,phosphite, phosphoramidite, or the like) and u can be 0 or 1 to 5. In anembodiment, MET can be bonded to one or more ligands. In an embodiment,the MET is bonded to a N, S, or O group in the B ring.

In an embodiment, the A ring (shown in the structure above) can be abenzenoid, a 5 or 6-membered heteroaromatic ring, or an aryl orheteroaryl fused-ring system (e.g., including 5 and/or 6 memberedrings). In an embodiment, the A ring can be an aryl group. In anembodiment, each of the R₅ groups is independently selected from:hydrogen, a halogen group, a cyclic or linear, alkyl group, an arylgroup, a —OR group, a —SR group, a —SiR₃ group, a NR₂ cyclic or lineargroup. In an embodiment, each R₅ group can be a halogen such as F. In anembodiment, R can be selected from: hydrogen, a cyclic or linear, alkylgroup, or an aryl group, wherein n is 1 to 5. In an embodiment X can beCR₂ or SO₂, where each R group is independently selected.

In an embodiment, the B ring (shown in the structure above) can beselected from a 5-member or fused-ring heteroaromatic system (e.g.,including 5 and/or 6 membered rings). In an embodiment, the B ring caninclude 1 to 5 N, S, O, or a combination of atoms in the ring(s). In anembodiment, the B ring can include 2 N atoms in a 5-memberedheteroaromatic ring. In an embodiment, the B ring can include one ormore moieties (“R” groups, such as R₁ and R₂ described herein) bonded tothe ring(s).

In an embodiment, the C ring (shown in the structure above) can be abenzenoid, a 5 or 6-membered heteroaromatic ring, or an aryl orheteroaryl fused-ring system (e.g., including 5 and/or 6 memberedrings). In an embodiment, the C ring can include an aryl fused-ringsystem (e.g., naphthyl group). In an embodiment, the R₃ groups can beindependently: hydrogen, a cyclic or linear, alkyl group, an alkoxide, aphenoxide, an aryl group, or a substituted amine. In an embodiment, eachR₃ group, independently, can be an aryl group such as phenyl.

In an embodiment, the biaryl compound can include any combination of:the A ring can be an aryl group, each R₅ group can be a halogen (e.g.,F), the B ring can include 1 to 5 N, S, and/or O atoms in the ring(s) orthe B ring can include 2 N atoms in a 5-membered heteroaromatic ring,the C ring can include an aryl fused-ring system, and/or each R₃ groupcan be an aryl group (e.g., phenyl).

In an embodiment, the biaryl compound can have the following structure(or shown bonded to a metal):

In an embodiment, the A ring (shown in the structure above) can be abenzenoid, a 5 or 6-membered heteroaromatic ring (not shown), or an arylor heteroaryl fused-ring, system (not shown). In an embodiment, the Aring is a phenyl group. In an embodiment, each of the R₅ groups canindependently be: hydrogen, a halogen group, a substituted orunsubstituted, cyclic or linear, alkyl group, a substituted orunsubstituted aryl group, a —OR group, a —SR group, a —SiR₃ group, a NR₂cyclic or linear group. In an embodiment, R can be: hydrogen, asubstituted or unsubstituted, cyclic or linear, alkyl group, or asubstituted or unsubstituted aryl group. In an embodiment, each R₅ groupcan be a halogen such as F. Subscript n can be 1 to 5. In an embodiment,X can be C or S. In an embodiment, each R₆ and R₇ group can beindependently: hydrogen, a substituted or unsubstituted, cyclic orlinear, alkyl group, a substituted or an unsubstituted aryl group. In anembodiment, R₆ and R₇ can be hydrogen.

In an embodiment, the B ring (shown in the structure above) can be a5-member or a fused-ring heteroaromatic (not shown) system. Q1, Q2, Q3,Q4, and Q5 are each independently selected. In an embodiment, at leastone of Q1, Q2, Q3, Q4, and Q5 can be N, O, or S, and the other of Q1,Q2, Q3, Q4, and Q5 can be C, N, O, or S. In an embodiment, the B ringcan be a 5-membered ring having one N atom and one O or S atom. In anembodiment, the B ring can include 1 to 5 N atoms or 2 to 5 N atoms, inparticular, the B ring is a 5-membered ring having 2 N atoms. In anembodiment, a combination of N, O, and/or S atoms can be used in the5-member or fused-ring heteroaromatic system, where atoms that are notN, O, or S atoms are carbon atoms.

In an embodiment, the biaryl compound structure can include one of thefollowing embodiments:

where the R groups can be those described herein and positioned as notedherein and the P group is positioned on the C ring such as noted herein.

In an embodiment, each R₁ and R₂ group can independently be selectedfrom: hydrogen, a halogen group, a substituted or unsubstituted, cyclicor linear, alkyl group, a substituted or unsubstituted aryl group, a —ORgroup, a —SR group, a —SiR₃ group, a NR₂ cyclic or linear group. In anembodiment, each of R₁ and R₂ can be an aryl group such as a phenylgroup. In an embodiment, R can be: hydrogen, a substituted orunsubstituted, cyclic or linear, alkyl group, or a substituted orunsubstituted aryl group.

In an embodiment, the C ring (shown in the structure above) can be abenzenoid, a 5 or 6-membered heteroaromatic ring, or an aryl orheteroaryl fused-ring, system. In an embodiment, the C ring can be anaphthyl group including the P group and R₄. In an embodiment, each ofthe R₄ groups can independently be selected from: hydrogen, a halogengroup, a substituted or unsubstituted, cyclic or linear, alkyl group, asubstituted or unsubstituted aryl group, a —OR group, a —SR group, a—SiR₃ group, a NR₂ cyclic or linear group. In an embodiment, each of theR₄ groups is hydrogen. Subscript n can be 1 to 5. In an embodiment, Rcan be: hydrogen, a substituted or unsubstituted, cyclic or linear,alkyl group, or a substituted or unsubstituted aryl group. In anembodiment, each of the R₃ groups can independently be selected from:hydrogen, a cyclic or linear, alkyl group, alkoxides, phenoxides, arylgroups, or substituted amines. In an embodiment, each R₃ can be an arylgroup such as a phenyl group.

MET refers to a metal such as, but not limited to, transition metals,Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, Pt, Cu, Au, or the like, where z can be1 to 3. L refers to a ligand (e.g., amide, phenolate, thiolate, halogen,carboxylate, acetylacetonate, phosphine, phosphite, phosphoramidite, orthe like) and u can be 0 or 1 to 5. In an embodiment, MET can be bondedto one or more ligands. In an embodiment, the MET is bonded to a N, S,or O group in the B ring, where the position can depend upon the Q1, Q2,Q3, Q4, and Q5. The bond to the B ring is shown as to the center of theB ring, and this indicates that the bond can be to any one of Q1, Q2,Q3, Q4, and Q5, and in particular, to Q5.

In an embodiment, the biaryl compound can have the following structure(or bonded to a metal):

In an embodiment, each R₅ can be a halogen such as F. In an embodiment,each R₃ group can be an aryl group such as a phenyl group. In anembodiment, each of R₁ and R₂ can be an aryl group such as a phenylgroup. In an embodiment, each R₄ is hydrogen. MET refers to a metal suchas a transition metal, Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, Pt, Cu, Au, orthe like, where z can be 1 to 3. L refers to a ligand (e.g., amide,phenolate, thiolate, halogen, carboxylate, acetylacetonate, phosphine,phosphite, phosphoramidite, or the like) and u can be 0 or 1 to 5. In anembodiment, MET can be bonded to one or more ligands.

In an embodiment, the biaryl compound can include the following:

In an embodiment, each of the biaryl compounds described herein can be amixture of enantiomers (e.g., a racemic mixture) or can be a singleenantiomer. In an embodiment, a racemic mixture can be deracemized byformation of a single diastereomer of complex with chiral palladiumcomplex. The decomplexation of the complex to release the biaryl ligandin high ee and chemical yield can be achieved under appropriateconditions, such as those described in the Examples. In addition,conducting the reaction at low temperature provides the biaryl ligand athigh ee and is highly reproducible. This biaryl ligand isconfigurationally stable and the follow provides an efficient method forits preparation as a single enantiomer (both enantiomers are readilyavailable). Additional details regarding the methods for forming asingle enantiomer are described in the Examples.

A method of making the biaryl compound having following structure:

can include the following general scheme.

wherein the solvents and reagents used can be substituted with knownequivalent solvents and/or reagents to accomplish the same or similarresults of forming the biaryl compound.

In an embodiment, a biaryl compound of the present disclosure can beformed using the following reaction sequence:

where other alternative reactants and solvents can be used as notedabove to form the biaryl compound. The racemic mixture can bederacemized by formation of a single diastereomer as shown below:where the reactants and solvents can be replaced with appropriatecompounds to produce the single diastereomer product. Additional detailsare provided in the Examples.

As noted above, biaryl compounds, such as

or the biaryl complex counterparts can be used as a catalyst (e.g.,asymmetric catalysis). In particular, the biaryl compounds can be usedin reactions such as: an enantioselective transformation, anenantioselective A³ coupling, an alkyne addition asymmetric allylicalkylation, an addition to an aliphatic or an aromatic aldehyde. Forexample, the following are exemplary reactions, where “7” can includeanyone of the compounds represented by

or “7” can be the compound noted as “7” in Example 3. In addition, otheralternative solvents and reactants can be used in place of the shownsolvents and reactants as long as they produce the desired product.

In an embodiment, enantioselective A³ coupling can be accomplished usingembodiments of the biaryl compound, as shown in the reaction below:

where R can include groups shown in Table 1, Example 3.

In an embodiment, an alkyne addition reaction can be accomplished usingembodiments of the biaryl compound, as shown in the reaction below:

80%, 92% ee 69%, 93% ee, where R is selected from SiMe₃ and Ph.

In an embodiment, an enantioselective A³ coupling can be accomplishedusing embodiments of the biaryl compound, as shown in the reactionbelow:

Now having described embodiments of the present disclosure in general,the following provides more details regarding embodiments of the biarylcompounds, methods of making biaryl compounds, and methods using biarylcompounds.

EXAMPLES

Now having described the embodiments of the disclosure, in general, theexample describes some additional embodiments. While embodiments of thepresent disclosure are described in connection with the example and thecorresponding text and figures, there is no intent to limit embodimentsof the disclosure to these descriptions. On the contrary, the intent isto cover all alternatives, modifications, and equivalents includedwithin the spirit and scope of embodiments of the present disclosure.

Example 1

Introduction

A multitude of academic and industrial processes rely on chiral ligandsto establish the stereocenters in fine chemicals.¹ For example, TakasagoInternational produces approximately 3,000 tons of menthol per yearusing an enantioselective hydrogenation reaction with BINAP as a chiralligand (see structure below).² BINAP belongs to a family of ligandscalled atropisomers, where the molecule is rendered chiral by restrictedrotation about a sigma-bond, as illustrated by the lack of chiralcenters in the molecules below.

Transition metal complexes ligated with BINAP function so incrediblywell, in such a vast number of different reactions that it is referredto as a privileged ligand,³ and many structural variants are built uponthis ligand's framework.^(2c) The phosphorous atoms have been changed toother heteroatoms such as oxygen and nitrogen to produce ligands such asBINOL and KenPhos. More significantly, the aromatic systems have beenmodified to benzenoid aromatics (BIPHEP) and heteroaromatics (QUINAP,PINAP).^(4,5) In practice, these types of modifications are made toincrease the enantioselectivity in a given reaction and, as aconsequence, an extremely large number of structural variants with smallmodifications have been prepared.^(2c) These incrementally modifiedligands have been successful in many cases, but can be very difficultand costly to prepare when a ligand such as a modified QUINAP ($1,700/g)is needed. More importantly, this strategy has resulted in a significantstructural homology within this class of ligands, namely the two arylrings of the biaryl are always 6-membered aromatics or fused 6-memberedaromatic systems. This limits the steric and electronic tuning of thesecompounds and severely restricts the spectrum of known aromatic systems,which are rife with chemical diversity, to what is available with6-membered ring systems. Herein we disclose a novel strategy to accessnew 5-membered heteroaromatic biaryls, demonstrate proof of principle,prepare highly enantioenriched ligands, and substantiate our claim thatthe ligands will be highly effective in enantioselective transformationswith several examples.

BACKGROUND

A perfect ligand system for enantioselective transformations would beable to accommodate both small and large substrates in the “chiralpocket” and impart high selectivity across a range of reactants.Unfortunately, the current state-of-the-art often requires highly tunedcongeners to modulate the steric demand in the chiral space about thereactive center to achieve this goal. In principle a “tighter”, moresterically demanding, chiral pocket would be needed for smallersubstrates and a more open reactive site for larger substrates. While itis easy to increase the steric demand, it is difficult to decrease itand maintain chirality, as described below. With chiral biaryl ligands,in the majority of these structures, rotation about the aryl-aryl σ-bondis hindered by ortho-substituents. As seen in FIG. 1.1, these groupsclosely protrude into each other's space. It follows that the mostcommon strategy for increasing the barrier to rotation is increasing thebulk of the substituents. Rotation about the aryl-aryl σ-bond is alwaysrestricted by steric interactions between substituents, which alsofunction to influence enantioselectivity. To accommodate bulkysubstrates, the size of the ortho substituents could be reduced but thisreduces the biaryl's barrier to rotation. As such, the potential ofbiaryls bearing less sterically demanding groups and compounds withsubstantially different structures remains unknown.

A high barrier to rotation due to ortho-substituents relies on both theidentity of the substituents and also the bond angles that orient thesubstituents in close proximity to each other.⁶ As can be seen in FIG.1.2, when 1 is rotated about the biaryl axis, R₁ approaches R₂ (or R₃).Since R₁ and R₂ are separated by 5 bonds, changes in bond angles indifferent aryl ring systems change the extent of the stericinteractions. In comparing pyrrole 2 to benzene 1, it can be seen thatR₂ and R₃ are much closer to the neighboring aryl ring in 1 than in 2.The 5-membered ring expands the ideal R₂—C—N bond angle to 126° incomparison to the 120° in benzene. This moves the groups apart, reducingsteric interactions. A countless number of 5-membered heteroaromaticswith varied steric and electronic properties are known, but thisdifficulty hinders their incorporation into biaryl ligands. This ishighly unfortunate because heterocycles are much more easily preparedand modified than benzenoid aromatics.

We became interested in this area because changing the bond angles ofthe aromatic systems would also allow for a previously unexplored designmodification of the chiral pocket, possibly creating a larger chiralspace and most certainly a different class of ligand. Intriguing workfrom Brown and co-workers on QUINAP derivatives demonstrated that indole3 and metal complexes thereof racemize rapidly (FIG. 1.3).⁷ Although5-membered biaryl heterocycles such as 3 are predicted to be usefulligands, they cannot be prepared enantiomerically pure. Increasing thesteric bulk could overcome this, but is counterproductive to preparingligands to accommodate larger substrates, which necessitates a newinnovative strategy.

While steric effects are important for catalysis, the conformation ofbiaryls is also important because changing the dihedral angle θ₁ byrotation about the aryl-aryl bond (arrow a) influences theligand-metal-ligand bite angle θ₂ as shown in FIG. 1.4.⁸ Changing from6- to 5-membered aromatics (e.g. QUINAP vs. 3) alters the bond anglesand would be predicted to cause a significant change in the bite angleby moving the chelating groups “outward”. This is schematicallyrepresented by the b arrows in FIG. 1.4, but systematic studies arelacking because altering the bond angles by “opening up” thesubstituents also reduces the barrier to rotation leading to loss ofchirality.

Employing heterocyclic chiral biaryls has two other salient features ofnote. Firstly, heterocyclic phosphines have been reported to be greatlybeneficial in many instances, such as the use of tri(2-furyl)phosphinein Heck reactions.⁹ The second advantage is that the literature is richwith methods for the synthesis of heterocycles with a high degree ofchemical diversity, suggesting that modular syntheses of a series ofhighly tunable ligand families will be available.

These potential applications suggest a fundamental question: How canaromatics with different ring sizes be incorporated into biaryls withsufficiently high barriers to rotation? More broadly, is there a novelstrategy or design principle other than steric obstruction of bondrotation that could be employed? Graphically represented in FIG. 1.5,the strategy of increasing steric interactions to increase the barrierto rotation is like moving from energy curve a for racemization to onefitting b. If stabilizing interactions that favor the chiral groundstate conformation were built into the structure, rotation about thesigma-bond would require that the energy contribution from theseinteractions also be overcome. This is like moving from energy curve ato c. By stabilizing the ground state, the barrier to rotation is alsoincreased. Surprisingly, this simple concept has not been explored. Theresearch outlined in here explores this premise in the context ofdesigning new ligands and catalysts.

Results Our central hypothesis is that the barrier to rotation in biarylsystems can be increased by incorporating design elements that stabilizethe ground state of these molecules. The stabilizing interactionexplored here is π-stacking, but π-cation interactions, hydrogen bondinginteractions, or even the introduction of covalent bonds can also beenvisioned to serve this purpose.¹⁰ As can be seen in FIG. 1.6, oursystem is comprised of biaryl rings A and B, and a C-ring appended forπ-stacking. The system will be in equilibrium between a planarconformation 4 (A and B planar) or stacked conformation 5 (A and Cπ-stacked). Our supposition is that conjugation and π-stacking willcause 4 and 5 to be energy minima and our hypothesis is that stabilizinginteractions in 5 will render this the lowest energy conformation.

Instead of relying on chiral probes to determine racemization rates,this system has the advantage that the appearance of H_(a) and H_(b) in4 and 5 should be diagnostic in the ¹H NMR. In 4, H_(a) and H_(b) areenantiotopic and therefore would appear as a singlet, while in 5, H_(a)and H_(b) are diastereotopic with unique signals in the ¹H NMR spectrum.The difference in ¹H NMR spectra should make identifying whichconformation is present straightforward, but also is advantageousbecause the barrier to rotation should be easily measured using variabletemperature NMR methods.¹¹ Additionally, there is no need to prepareenantiomerically pure samples and the method is non-destructive so thebarrier can easily be measured in a variety of solvents without the needfor a new sample. The only requirement for use of the coalescence methodis that H_(a) and H_(b) must be distinct signals that coalesce.

To test this hypothesis we chose model compounds 10 and 11 forcomparison. These biaryl compounds were easily prepared from boronicacid 6¹² and bromonaphthalene 7 (Scheme 1.1), Suzuki coupling¹³ provided8, which was deprotected¹⁴ to give 9 in 59% yield over two steps. Thedesired biaryl 11 was then accessed by simple benzylation. From 9, thepentafluorophenyl compound 33 was also readily prepared.

These two compounds are the basis for the initial test of ourhypothesis. It is important to determine the portion of the barrier torotation that can be attributed to i-stacking and how much inherent tothe system. For this, pairs of compounds such as 10 and 11 need to beemployed. Since fluorine and hydrogen are similar in size,¹⁵ thedifference in barrier height, ΔΔG^(‡), can be interpreted as theelectronic contribution and attributed to π-stacking.

As can be seen in the ¹H NMR spectra (FIG. 1.7), the benzylic protonsare a singlet in 11 and an AB pattern in 10. On the NMR timescale, thereis free rotation about the aryl-aryl bond in 11, while rotation isrestricted in 10. This demonstrates that changing the electronics of thesystem can bias the conformation to give the non-conjugated arrangementwith smaller aromatic rings without bulky ortho-substituents. Thebarrier to rotation was determined and the coalescence temperature isstrikingly different (FIG. 1.8). While the signals in 11 coalesce at 9°C., 10 had to be heated to 57° C. From these data, the barrier torotation for 11 in CDCl₃ is 13.9 kcal/mol and for 10, 16.3 kcal/mol.

The spectrum indicates that 10 is not planar and the barrier dictatesthat it is not locked in a single conformation in solution. To gainfurther evidence of π-stacking, an X-ray structure was obtained (FIG.1.9). The dihedral angle between the A- and B-rings is 880 and the A-and C-rings are π-stacked with a distance of 3.26 Å. The stacking isparallel and offset, but the rings are not perfectly parallel with theC-ring slightly canted away from the naphthalene. Similar experimentswere also performed on fluorinated and non-fluorinated indolederivatives and the results were quite surprising. Interestingly, thecoalescence temperatures are much higher with indoles (FIG. 1.10). Toreach coalescence, 12 required heating to nearly 80° C.; a 17.6 kcal/molbarrier. It was previously thought that the B-ring linker would notinfluence the barrier height. This result clearly indicates the contraryand suggests that varying the heterocyclic B-ring is a worthy endeavoras it is a significant contributor to the barrier height.

We now have several pairs of heterocyclic biaryls(fluorinated/non-fluorinated). In each case the fluorinated, π-stackedcompounds have a higher barrier to rotation. It is important to notethat a barrier height of 17.6 kcal/mol is not sufficient foratropisomerism. However, these model studies demonstrate that π-stackingis indeed possible and that it increases the barrier height by ˜2-3kcal/mol. In functional molecules, there will be an increase in thesteric component and inclusion of the π-stacking aryl group will providean additional ˜2-3 kcal/mol. Additionally, π-stacking should positionthe substituent away from the reactive center, furthering the goal ofproviding a chiral biaryl ligand that can accommodate larger substrates.

Results—Ligands and Catalysts

While the model compounds demonstrate that the concept is feasible, nofunctional groups are built into the molecules for further applications.There are a small number of known biaryl, C₂-symmetric, bis-phosphineligands with 5-membered aromatics but these utilize traditional stericinteractions to render them atropisomeric.^(2c) As stated above, ourinterest in this area stems from the hypothesis that relativelyunhindered C₁-symmetric compounds such as 3 ^(7,16) (for which noreactions are currently known due to configurational instability) willbe excellent ligands in enantioselective reactions.

Synthesis and Configurational Stability: We decided to prepare the novelphosphine-substituted imidazole 18 as it should be chiral and functionas a P,N-ligand for enantioselective transformations (Scheme 1.2). Thesynthesis begins with commercially available 14 and after severalstraightforward steps provides triflate 17. Interestingly, 16 is chiraland its enantiomers can be separated by HPLC, but the correspondingnon-fluorinated analogue is achiral with a coalescence temperature of94° C. Conversion of 17 to 18 was accomplished by Ni-catalyzedcross-coupling.¹⁷ This synthesis is scalable (multigram) and largequantities of the ligand are available.

With a good source of the racemic ligand in hand, what remains forapplications in enantioselective catalysis is determination of theconfigurational stability, resolution of the enantiomers, andpreparation of metal complexes. P,N-ligands such as QUINAP andderivatives are commonly resolved by complexation with a chiralPd-complex, separation of the diastereomers, and decomplexation toreveal the enantiomers of the ligand.^(4,7,18) This route is fairlywasteful as a chiral complex is needed to recover half of the material.This is likely the reason for the high cost of QUINAP. As a firstattempt, resolution was attempted using the same method. Unfortunately,all attempts to separate the enantiomers resulted in less than adequateresults. This drove us to study the dynamic behavior of the ligand.Interestingly, we discovered that instead of resolution and recovery ofhalf the material, all of the material could be converted to a singlediastereomer of the ligand. Accordingly, the ligand 18 is converted totwo diastereomeric palladium complexes by simply stirring with 19,however upon refluxing in acetone overnight, 20 is isolated as a singlediastereomer as judged by ¹H NMR spectroscopy (Scheme 1.3).

Free, deracemized ligand is then readily liberated from complex 20 bytreatment with dppe to provide scalemic 21 in 88% ee (94:6 enantiomericratio). The ee of the ligand is readily determined by oxidation of thephosphine to the phosphine oxide and analysis by HPLC using a chiralstationary phase (Scheme 1.4).

For use as a ligand, the ee needs to be increased even further. Usingthis recrystallization procedure, the ligand has been obtained in 97% eeand a superior procedure is outlined in Example 2.

Several important points warrant mention. Firstly, the free ligand isconfigurationally stable. The free ligand can be stored indefinitely asa solid without any decrease in ee. We have tested samples over severalmonths now and see no indication of loss of ee. Secondly, the C-ring isπ-stacked in the free ligand as can be seen in the crystal structure inFIG. 1.11.

Furthermore, we were able to obtain a crystal structure of the palladiumcomplex 20. Much to our surprise, the X-ray structure of 20 revealedthat this complex presents chiral space similar to that observed inBINAP complexes, which function well in an extremely large number ofenantioselective reactions. This was unexpected as the ligands areextremely different in structure. As can be seen in FIG. 1.12, twophenyl groups (wireframed) adopt a propeller-like orientation about themetal center (Pd; pink) with empty space in the NE and SW quadrants. InBINAP-complexes, enantiodifferentiation is attributed to thisarrangement. BINAP is a C₂-symmetric bis-phosphine with the opencoordination sites being equivalent. Here we also have electronicdifferentiation of the coordination sites trans to P and N atoms,further controlling the chiral space for catalysis.

The data above demonstrates that heterocyclic biaryls with 5-memberedring components can be easily prepared, rendered chiral withoutincorporation of bulky ortho-substituents, prepared in optically pureform, and incorporate functional groups for use as ligands. What remainsis demonstration that these compounds can effectively be used as ligandsto catalyze enantioselective transformations. With ligand 21 in hand,some preliminary screening was done to see if it can induceenantioselectivity. Asymmetric allylic alkylation was chosen so thatcomparison could be made to QUINAP and BINAP, which have been referencedextensively above. Employing enantiopure BINAP and QUINAP, the productis obtained in 90% and 95% ee respectively (Scheme 1.5).¹⁹ Using 21 (92%ee), the ee of the product is 89%. It should be noted that none of theseare the best ligand for this specific transformation, but these datademonstrate that the ligands are effective at inducingenantioselectivity: 92% ee 21 functions as well as enantiopure BINAP andshould surpass it when the ee is the same.

We are interested in using these complexes to address limitations incurrent state-of-the-art systems. Knochel has reported employing QUINAPin three-component reactions.²⁰ Aromatic aldehydes were the mostchallenging substrates in his reports, displaying low reactivity andenantioselectivity. In these reactions ligand 21 was employed and usingthis novel compound in 87% ee (obtained prior to learning how toincrease it's ee) it outperformed enantiopure QUINAP in both reactivityand selectivity (Scheme 1.6). Using our ligand in 87% ee, both electrondeficient and electron rich aromatic aldehydes function well in thereaction. This is in contrast to the current stat-of-the-art where thereactions are low yield after long reaction times and provide theproducts in low enantiomeric excess. With this increased reactivity, itis likely that lower reaction temperatures can be employed.

As can be seen in Scheme 1.7, we have also worked on aliphaticaldehydes, with success. Using our ligand, now in 97% ee, the reactionfunctions quite well providing the product in 96% ee. It should be notedthat this reaction was performed at 0° C. and was complete in 24 h.

The reaction was also performed using aromatic aldehydes, dibenzylamine,and trimethylsilyl acetylene with ligand 21 in 97% ee. Again highchemical and optical yield was observed.

As can be seen above, ligand 21 functions extremely well and this iscurrently the most reactive and appears to be the most highly selectivesystem for the so-called A³-coupling reaction.²¹

The true power of this strategy is the ability to readily prepareinteresting new ligand classes using this design principle. The currentstructure is also highly modular and one could envision a myriad ofmodifications that could easily be prepared (FIG. 1.13).

In summary, we have prepared anew class of 5-membered heteroaromaticligands with the ground state stabilized via π-stacking. These ligandsare readily prepared, isolated in high ee, are configurationally stable,and function to impart high ee in organometallic reactions.Additionally, they are highly modular and can be readily modified foreither fine-tuning or to create a variety of different types of novelligand classes.

REFERENCES

-   1. Noyori R. (Ed.), Asymmetric Catalysis in Organic Synthesis,    Wiley, New York, 1994.-   2. A) Noyori, R.; Takaya, H. BINAP: An Efficient Chiral Element for    Asymmetric Catalysis. Acc. Chem. Res. 1990, 23, 345-350. B) Berthod,    M.; Mignani, G.; Woodward, G.; Lemaire, M. Modified BINAP: The How    and the Why. Chem. Rev. 2005, 105, 1801-1836. C) Shimizu, H.;    Nagasaki, I.; Saito, T. Recent advances in biaryl-type bisphosphine    ligands. Tetrahedron 2005, 61, 5405-5432.-   3. A) Yoon, T. P.; Jacobsen, E. N. Privileged Chiral Catalysts.    Science 2003, 299, 1691. B) Qi-Lin Zhou (Ed.), Privileged Chiral    Ligands and Catalysts, Wiley-VCH, Weinheim, 2011.-   4. Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Synthesis and    Resolution of 1-(2-Diphenylphosphino-lnaphthyl)isoquinoline; a P—N    Chelating Ligand for Asymmetric Catalysis. Tetrahedron: Asymmetry    1993, 4, 743-756.-   5. Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;    Carreira, E. M. Readily available biaryl P,N ligands for asymmetric    catalysis Angew. Chem., Int. Ed. 2004, 43, 5971-5973.-   6. Alkorta, I.; Elguero, J.; Roussel, C.; Vanthuyne, N.; Piras, P.    Atropisomerism and Axial Chirality in Heteroaromatic Compounds. Adv.    Heterocycl. Chem. 2012, 105, 1-188.-   7 Claridge, T. D. W.; Long, J. M.; Brown, J. M.; Hibbs, D.;    Hursthouse, M. B. Synthesis of    1-Methyl-2-diphenylphosphino-3-(1′-isoquinolyl)indole; an Easily    Racemised Ligand giving Insights into Catalytic Asymmetric    Allylation. Tetrahedron 1997, 53, 4035-4050.-   8. Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M. Bite angle    effects of diphosphines in C—C and C—X bond forming cross coupling    reactions. Chem. Soc. Rev., 2009, 38, 1099-1118.-   9. Andersen, N. G., Keay, B. A. 2-Furyl Phosphines as Ligands for    Transition-Metal-Mediated Organic Synthesis Chem. Rev. 2001, 101,    997-1030.-   10. A) Meyer, E. A., Castellano, R. K.; Diederich, F. Interactions    with Aromatic Rings in Chemical and Biological Recognition. Angew.    Chem., Int. Ed. 2003, 42, 1210-1250; B) Salonen, L. M., Ellermann,    M., Diederich, F. Aromatic Rings in Chemical and Biological    Recognition: Energetics and Structures. Angew. Chem., Int. Ed 2011,    50, 4808-4842.-   11 Sutherland, I. O. The investigation of the kinetics of    conformational changes by nuclear magnetic resonance spectroscopy.    Annu. Rep. NMR Spectrosc. 1971, 4, 71-235.-   12. Haynes, S. W.; Sydor, P. K.; Stanley, A. E.; Song, L.;    Challis, G. L. Role and substrate specificity of the Streptomyces    coelicolor RedHenzyme in undecylprodiginine biosynthesis. Chem.    Commun., 2008, 1865-1867.-   13. Clift, M. D.; Thomson, R. J. Development of a Merged Conjugate    Addition/Oxidative Coupling Sequence. Application to the    Enantioselective Total Synthesis of Metacycloprodigiosin and    Prodigiosin R1. J Am. Chem. Soc. 2009, 131, 14579-14583.-   14. Hasan, I.; Marinelli, E. R.; Lin, L. C. C.; Fowler, F. W.;    Levy, A. B. Synthesis and Reactions of N-Protected 2-Lithiated    Pyrroles and Indoles. The tert-Butoxycarbonyl Substituent as a    Protecting Group. J. Org. Chem. 1981, 46, 157-164.-   15. Schlosser, M.; Michel, D. Introduction of fluorine into organic    molecules: why and how. Tetrahedron 1996, 52, 99-108.-   16. Figge, A., Altenbach, H. J., Brauerb, D. J., Tielmannc, P.    Synthesis and resolution of    2-(2-diphenylphosphinyl-naphthalen-1-yl)-1-isopropyl-1Hbenzoimidazole;    a new atropisomeric P,N-chelating ligand for asymmetric catalysis.    Tetrahedron: Asymmetry 2002, 13, 137-144.-   17. Kwong, F. Y.; Chan, A. S. C.; Chan, K. S. Chelating Retardation    Effect in Nickel Assisted Phosphination: Syntheses of Atropisomeric    P,N Ligands. Tetrahedron 2000, 56, 8893-8899.-   18. A) Otsuka, S.; Nakamura, A.; Kano, T.; Tani, K. Partial    Resolution of Racemic Tertiary Phosphines with an Asymmetric    Palladium Complex. J. Am. Chem. Soc. 1971, 93, 4301-4303; B) Tani,    K.; Brown, L. D.; Ahmed, J.; Ibers, J. A.; Yokota, M.; Nakamura, A.;    Otsuka, S. Chiral Metal Complexes. 4. Resolution of Racemic Tertiary    Phosphines with Chiral Palladium(II) Complexes. The Chemistry of    Diastereomeric Phosphine Pd(II) Species in Solution, and the    Absolute Configuration of    [(S)-Isopropyl-tert-butylphenylphosphine]-[(R)—N,N-dimethyl-a-(2-naphthyl)-ethylamine-3C,N]chloropalladium(II)    Determined by X-Ray Diffraction. J. Am. Chem. Soc. 1977, 99,    7876-7886. C) Allen, D. G.; Mclaughlin, G. M.; Robertson, G. B.;    Steffen, W. L.; Salem, G.; Wild, S. B. Resolutions with metal    complexes. Preparation and resolution of    (R,S)-methylphenyl(8-quinolyl)phosphine and its arsenic analog.    Crystal and molecular structure of    (+)₅₈₉-[(R)-dimethyl(1-ethyl-naphthyl)aminato-C²,N][(S)-methylphenyl(8-quinolyl)phosphine]palladium(II)    hexafluorophosphate. Inorg. Chem. 1982, 21, 1007-1014.-   19. A) Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Mechanistic and    Synthetic Studies in Catalytic Allylic Alkylation with Palladium    Complexes of 1-(2-Diphenylphosphino-1-naphthyl)isoquinoline.    Tetrahedron 1994, 50, 4493-4506. B) Yamaguchi, M.; Shima, T.;    Yamagishi, T.; Hida, M. Palladium-catalyzed asymmetric allylic    alkylation using dimethyl malonate and its derivatives as    nucleophile. Tetrahedron: Asymmetry 1991, 2, 663-666.-   20. A) Gommermann, N.; Koradin, C.; Polbom, K.; Knochel, P.    Enantioselective, Copper(I)-Catalyzed Three-Component Reaction for    the Preparation of Propargylamines. Angew. Chem. Int. Ed 2003, 42,    5763-5766; B) Gommermann, N.; Knochel, P. Practical Highly    Enantioselective Synthesis of Propargylamines through a    Copper-Catalyzed One-Pot Three-Component Condensation Reaction.    Chem. Eur. J. 2006, 12, 4380-4392.-   21. Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. A walk    around the A³-coupling. Chem. Soc. Rev. 2012, 41, 3790-3807.-   22. McCartney, D.; Guiry, P. J. The asymmetric Heck and related    reactions. Chem. Soc. Rev. 2011, 40, 5122-5150.-   23. Marion, N.; Diez-Gonzalez, S.; Nolan, S. P. N-heterocyclic    carbenes as organocatalysts Angew. Chem., Int. Ed. 2007, 46,    2988-3000.

Example 2

One challenge outlined above centers around isolating the ligand in highenantiomeric excess. The following shows conditions that reproduciblyprovide the ligand in 98% ee. As can be seen in FIG. 2.1, the racemicligand 1 can be deracemized by formation of a single diastereomer ofcomplex 3 with chiral palladium complex 2 at 60° C. The development isthat decomplexation of 3 to release the ligand 4 in high ee and chemicalyield can be achieved under the illustrated conditions. Running thereaction at low temperature is provides 4 in 98% ee that isreproducible. This ligand is configurationally stable and the followprovides an efficient method for its preparation as a single enantiomer(both enantiomers are readily available).

Example 3

Brief Introduction

A new strategy for increasing the barrier to rotation in biaryls hasbeen developed that allows for the incorporation of 5-membered aromaticheterocycles into chiral atropisomers. Using this concept, animidazole-based biaryl P,N-ligand has been designed and prepared as asingle enantiomer. This ligand performs exceptionally well in theenantioselective A³ coupling, demonstrating the potential of this newdesign element.

Background

The chiral biaryl structural motif is an important component found in adiverse array of catalysts for enantioselective synthesis¹. Ligandsbuilt on the binaphthalene and biphenyl backbone are regularly employedin a variety of reactions with such success that BINAP 1 and BINOL arereferred to as privileged ligands¹. The atropisomeric backbone in thevast majority of chiral biaryl ligands is comprised of substituted orfused benzenoid aromatics that rely on ortho-substitution to hinderrotation about the biaryl bond.³ Although reducing the steric demand byremoving substituents from the 2- or 8-positions lowers the barrier torotation and hence reduces configurational stability,⁴ P,N-ligands suchas QUINAP 2⁵ and PINAP 3⁶ have successfully been prepared and employedin enantioselective transformations.^(7,8) It is well-known thatchanging the dihedral and bite angles of the biaryl can drasticallyaffect ligand performance and the success of 2 and 3 can be attributedto modifying these parameters as well as changing the donatingproperties of the ligand.⁹

Atropisomeric P,N-ligands have proven to be highly selective,⁷ butmaking structural modifica-tions for fine tuning of the ligand ischallenging and relatively few derivatives are known.⁸ In contrast tothe substituted or fused 6-membered aromatics commonly encountered,5-membered heteroaromatics would offer a new unexplored chemicaldiversity and be much easier to prepare and modify using establishedmethods.¹⁰ One potential problem is that ortho-substituents on5-membered rings are not held as closely in space to the adjacentaromatic group due to the modified bond angles of the ring-system. Thismay lead to a reduced barrier to rotation and loss of chirality. In hisseminal work, Brown encountered this difficulty when 4, an indoleversion of QUINAP, was prepared and found to not be configurationallystable (FIG. 3.1).¹¹ While this may potentially be overcome by theincorporation of increasingly large ortho-substituents,¹² the centraldogma for inducing atropisomerism, we hypothesized that a fundamentalnew approach to increasing the barrier to rotation could be developed toenable new classes of highly reactive and selective catalysts. Morespecifically, we hypothesized that the barrier to rotation in biarylscan be increased by stabilizing the chiral ground state conformationinstead of destabilizing the planar transition state leading toracemization (FIG. 3.1). Surprisingly, to the best of our knowledge,this strategy has never been explored. Herein we report our findings inthis area including the design, synthesis, deracemization, andsuccessful implementation of a chiral imidazole-based biaryl P,N-ligandfor enantioselective copper acetylide addition.

The design of our ligand centers around the in-corporation of a5-membered electron rich aromatic heterocycle that contains acoordinating atom and functional elements that stabilize the chiralconformation. At the outset we envisioned an imidazole-based system,providing a basic coordination site and a second nitrogen atom thatcould be appended with a group to stabilize the chiral conformation 7through π-stacking interactions (FIG. 3.2). This would provide a uniqueP,N-ligand with modified bite and dihedral angles.

The synthesis of racemic 7 was achieved in several straightforward stepsstarting with 2-hydroxy-1-naphthaldehyde 8, whereby the requisiteheterocycle and phosphino groups were readily introduced (FIG. 3.3). Inthe event, condensation of 8 with ammonium acetate and benzil furnished9 in 80% yield¹³. The free alcohol was then protected as the TBS etherand the resulting imidazole alkylated with pentafluorobenzyl bromide toyield 10. The alcohol was then deprotected, converted to the triflate,and coupled¹⁴ to produce rac-7 in ca. 33% overall yield from commercialmaterials. We were encouraged to find an AB pattern for the benzylicprotons in the ¹H NMR spectrum of rac-7, indicating that they arediastereotopic on the NMR timescale.

With a good source of 7 established, albeit racemic, it seemed prudentto perform a preliminary ligand acceleration effect study. To this end,rac-7 was employed in a copper-catalyzed A³-coupling¹⁵ of butyraldehyde,trimethylsilylacetylene, and dibenzylamine (eq. 1). Much to our delight,amine product 13 was isolated in 97% yield after 24 h at roomtemperature. Structurally, ligand 7 is significantly different than theknown biaryl P,N-ligands such as QUINAP where 13 is obtained in 88%after 120 h^(16,6). Extended reaction times of several days to a weekare commonly observed using these ligands.17 With rac-7, the reactivitywas enhanced to such an extent that the reaction could even be performedat 0° C., providing 13 in 92% yield after 24 h (eq. 1). This should beadvantageous for achieving high selectivities, and attempts were nextmade to obtain the ligand as a single enantiomer.

For QUINAP, and derivatives containing only axial chirality, non-racemicmaterial is typically obtained by resolution involving coordination to achiral Pd-salt, crystallization, and decomplexation^(5,11,18).Unfortunately, this strategy did not provide satisfactory results and 7could only be obtained in 85-90% ee. Fortunately, instead of resolving7, after extensive optimization it was found that the racemic compoundcould be converted to a single enantiomer in a two-step process, ineffect deracemizing it. To achieve this, rac-7 was treated with complex14 and KPF₆ in refluxing acetone for 24 h to provide 15 in 81% yield asa single diastereomer whose structure was confirmed by X-raycrystallography (FIG. 3.4)²⁰. The free ligand was then obtained in highyield and 98% ee after treatment with dppe.²¹

Interestingly, the inclusion of KPF₆ is vital to the success of thereaction as two non-interconverting diastereomers are observed in theabsence of this additive. Control experiments were performed to studythis issue and an equal mixture of two diastereomers is formed when KPF₆is omitted, but under otherwise identical reaction conditions.Additionally, re-complexation of 7 (98% ee) to 14 results in a singlediastereomer that does not revert to the same 1:1 mixture ofdiastereomers upon heating.

It is important to note that 7 is configurationally stable and samplesof the ligand have been stored for several months with no loss ofoptical purity. One further question regarding the structure involvesthe role of the C₆F₅ group and π-stacking. Evidence of π-stacking wasobtained early on when X-ray quality single crystals were grown from asample of rac-7 and the structure solved (FIG. 3.5) The F₅-phenyl groupis π-stacking with the naphthalene ring at a mean distance of 3.36 Å ina parallel, offset stack.²² This demonstrates that π-stacking ispossible in the solid state, but does not necessarily indicate that ithas any influence on the barrier to rotation in solution. Literatureprotocols used to study π-stacking involve modification of thesubstitution on one of the aromatic rings.²² To probe this issue, acomparison of barrier heights between 7 and a compound that wouldmaintain the steric profile but perturb the ability to π-stack wasneeded. In accord with literature precedent, the correspondingnon-fluorinated compound was chosen because if the effect was purelysteric, no significant difference would be expected. If π-stacking isindeed involved in the solution phase, a significant difference inbarrier height should be observed.

To make the necessary comparisons, 7-H₅ was prepared from 8 using theroute outlined above.¹⁹ Interestingly, the penultimate non-fluorinatedpalladium complex 15-H₅ was configurationally unstable, and the 1:1diastereomeric mixture of complexes prepared from racemic 7-H₅ convergedon a single diastereomer upon standing at room temperature for 24 h.When 7-H₅ was liberated from the Pd-complex, it was obtained in 52% ee,a stark contrast to 7 which was isolated in 98% ee. Racemization studieswere performed²³ on both 7-H₅ and 7 to obtain their barriers to rotationand it was found that 7-H₅ has a half life of 22 min at 75° C. in DCEwhereas 7 has a half-life of 8.70 h.¹⁹ This corresponds to ΔΔG^(‡)_(75° C.)=2.2 kcal/mol,¹⁹ which is a value that is within the range ofpreviously reported values for π-stacking²² and demonstrates that theelectronic perturbation by simple inclusion of the flourine atomssignificantly increases the barrier to rotation.

With this new chiral non-racemic ligand 7 in hand, attention was turnedto testing its performance in an enantioselective transformation. Tothis end, 7 was employed in the enantioselective A³ coupling. As can beseen in Table 3.1, the reactions were highly enantioselective over arange of aldehydes. As might be expected,¹⁵ with aliphatic aldehydesα-substitution increases selectivity (e.g. entry 1 vs. 4). It, is alsonoteworthy that, using 7, these conditions work well for aromaticaldehydes, which are the most challenging substrates for the reaction.¹⁷Remarkably, the presence of electron-donating or withdrawing groups havelittle effect on selectivity (entries 5-9), nor does the reactiontemperature. When 16 g was allowed to react at 0° C., the reaction wasvery slow, yielding 17 g in only 15% after 4 days, but in 95% ee (entry8). Increasing the temperature to 22° C. restored the reactivity to anacceptable level (70% yield after 24 h) and had little effect on the ee(entry 9). In comparison, the previous best yield obtained with thiselectron deficient aldehyde was 43% after 4 days to obtain the productin 63% ee.^(17a)

TABLE 3.1 Enantioselective A³-coupling employing 7.^(a)

yield ee entry aldehyde product (%)^(b) (%) 1

95 97^(c) 2

92 95^(c) 3

94 91 4

92 89^(c) 5

80 94^(c) 6

77 94^(d) 7

60 94^(c,d) 8 9

15 70 95^(c,d) 92^(c,e)

Carreira has also developed modified conditions to employ the amine 19,which is readily deprotected.²⁴ With these conditions, using the PINAPligand, they report that aromatic aldehydes do not provide satisfactoryresults.²⁴ In contrast, ligand 7 enables the use of both aliphatic andaromatic aldehydes with high enantioselectivity (FIG. 3.6). Theseresults lead to the conclusion that 7 is the best ligand for theenantioselective A³-coupling to date, displaying the highest levels ofreactivity and selectivity over the broadest range of substrates. Moreimportantly, these results demonstrate the potential of the new designelement exemplified by 7.

In summary, we have developed a new concept for increasing the barrierto rotation in biaryls whereby the chiral ground state conformation isstabilized by π-stacking interactions. This strategy was successfullyapplied to the design of ligand 7, a new chiral biaryl P,N ligandincorporating a 5-membered electron rich heteroaromatic. The ligand isstraightforward to prepare and has been demonstrated to be a superbcatalyst for the enantioselective A³ coupling reaction. Moreimportantly, this design concept should be broadly applicable and enablea new class of 5-membered heteroaromatic biaryls to be prepared ascatalysts for a range of reactions.

REFERENCES

-   1. (a) Comprehensive Asymmetric Catalysis, Vol. 1-3 (Eds.: E. N.    Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999. (b)    Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61,    5405-5432; (c) McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57,    3809-3844.-   2. (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299,    1691-1693. (b) Qi-Lin Zhou (Ed.), Privileged Chiral Ligands and    Catalysts, Wiley-VCH, Weinheim, 2011.-   3. (a) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345-350. (b)    Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005,    105, 1801-1836; (c) Brunel, J. M. Chem. Rev. 2005, 105, 857-897; (d)    Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155-3211.-   4. Oki, M. Top. Stereochem. 1983, 14, 1-76.-   5. (a) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron:    Asymmetry 1993, 4, 743-756; (b) Lim, C. W.; Tissot, O.; Mattison,    A.; Hooper, M. W.; Brown, J. M.; Cowley, A. R.; Hulmes, D I.;    Blacker, A. J. Org. Process Res. Dev. 2003, 7, 379-384.-   6. Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;    Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971-5973.-   7. For leading references on enantioseletive hydroboration, see: (a)    Carroll, A.; O'Sullivan, T. P.; Guiry, P. J. Adv. Synth. Catal.    2005, 347, 609-631; (b) Doucet, H.; Fernandez, E.; Layzell, T. P.;    Brown, J. M. Chem. Eur. J. 1999, 5, 1320-1330; For diboration: (c)    Morgan, J. M.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003,    125, 8702-8703; For conjugate addition: (d) Fujimori, S.;    Knopfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.;    Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635-1657; (e)    Knopfel, T. F.; Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am.    Chem. Soc. 2005, 127, 9682-9683; For [3+2] dipolar    cycloaddition: (f) Lim, A. D.; Codelli, J. A.; Reisman, S. E. Chem.    Sci., 2013, 4, 650-654; (g) Chen, C.; Li, X.; Schreiber, S. L. J.    Am. Chem. Soc. 2003, 125, 10174-10175; For allylic alkylation: (h)    Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tetrahedron 1994, 50,    4493-4506 and references cited therein.-   8. (a) Kostas, I. D. Curr. Org. Synth., 2008, 5, 227-249; (b)    Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346, 497-537.-   9. (a) Carroll, M. P.; Guiry, P. J.; Brown, J. M. Org. Biomol.    Chem., 2013, 11, 4591-4601; (b) Birkholz, M.-N.; Freixa, Z.; van    Leeuwen, P. W. N. M. Chem. Soc. Rev. 2009, 38, 1099-1118.-   10. Li, J. J. In Name Reactions in Heterocyclic Chemistry;    Wiley-VCH: Weinheim, 2004.-   11. Claridge, T. D. W.; Long, J. M.; Brown, J. M.; Hibbs, D.;    Hursthouse, M. B. Tetrahedron 1997, 53, 4035-4050.-   12. There are several reports of 5-membered aromatic chiral biaryl    ligands with bulky ortho-substituents. See: (a) Berens, U.;    Brown, J. M.; Long, J.; Selke, R. Tetrahedron: Asymmetry 1996, 7,    285-292; (b) Benincori, T.; Brenna, E.; Sannicolò, F.; Trimarco, L.;    Antognazza, P.; Cesarotti, E.; Demartin, F.; Pilati, T. J. Org.    Chem. 1996, 61, 6244-6251; (c) Benincori, T.; Brenna, E.; Sannicolò,    F.; Trimarco, L.; Antognazza, P.; Cesarotti, E.; Zotti, G. J.    Organomet. Chem. 1997, 529, 445-453; (d) Benincori, T.; Cesarotti,    E.; Piccolo, O.; Sannicolò, F. J. Org. Chem. 2000, 65,    2043-2047; (e) Benincori, T.; Piccolo, O.; Rizzo, S.;    Sannicolò, F. J. Org. Chem. 2000, 65, 8340-8347; (f) Andersen, N.    G.; Parvez, M.; Keay, B. A. Org. Lett. 2000, 2, 2817-2820; (g)    Benincori, T.; Gladiali, S.; Rizzo, S.; Sannicolò, F. J. Org. Chem.    2001, 66, 5940-5942; (h) Figge, A.; Altenbach, H. J.; Brauer, D. J.;    Tielmann, P. Tetrahedron: Asymmetry 2002, 13, 137-144 for leading    references. For a review see: (i) Alkorta, I.; Elguero, J.; Roussel,    C.; Vanthuyne, N.; Piras, P. Adv. Heterocycl. Chem. 2012, 105,    1-188.-   13. Eseola, A. O.; Obi-Egbedi, N. O Spectrochim. Acta A 2010, 75,    693-701.-   14. Kwong, F. Y.; Chan, A. S. C.; Chan, K. S. Tetrahedron 2000, 56,    8893-8899.-   15. (a) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V.    Chem. Soc. Rev. 2012, 41, 3790-3807; (b) Yoo, W.-J.; L. Zhao, L.;    Li, C.-J. Aldrichimica Acta 2011, 44, 43-51.-   16. Gommermann, N.; Knochel, P. Chem. Commun. 2004, 2324-2325.-   17. (a) Gommermann, N.; Koradin, C.; Polbom, K.; Knochel, P. Angew.    Chem. Int. Ed. 2003, 42, 5763-5766; (b) Gommermann, N.; Knochel, P.    Chem. Eur. J. 2006, 12, 4380-4392.-   18. Li, Y.-M.; Kwong, F.-Y.; Yu, W.-Y.; Chan, A. S. C. Coord. Chem.    Rev. 2007, 251, 2119-2144.-   19. Anderson, N. G. Org. Process Res. Dev. 2005, 9, 800-813.-   20. The ee of 7 was measured by HPLC after oxidation to the    corresponding phosphine oxide. See SI for detailed information.-   21. (a) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem.,    Int. Ed. 2003, 42, 1210-1250; (b) Salonen, L. M.; Ellermann, M.;    Diederich, F. Angew. Chem., Int. Ed. 2011, 50, 4808-4842; (c)    Gung, B. W.; Xue, X.; Zou, Y. J. Org. Chem. 2007, 72, 2469-2475.-   22. Muller, C.; Pidko, E. A.; Staring, A. J. P. M.; Lutz, M.;    Spek, A. L.; van Santen, R. A.; Vogt, D. Chem. Eur. J. 2008, 14,    4899-4905.-   23. Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M. Org. Lett.    2006, 8, 2437-2440.

Example 4

Ligand 7 from Example 3 above has been named StackPhos and this ligandhas been demonstrated to be excellent for enantioselectivecopper-catalyzed addition of acetylides to quinolinium salts, as seen inTable 4.1 below.

TABLE 4.1 Entry Solvent T [° C.] t [h] Yield [b][%] ee [%] 1 Toluene rt18 50 — 2 ACN rt 18 55 — 3 DCM rt 4 92 — 4 DCM rt 4 90 93 5 DCM   0° C.18 80 95 6 DCM −20° C. 22 74 98 [a] Entries 1-3 were performed withracemic ligand. [b] Yields of isolated products. Ligand = StackPhos

The scope of the reaction was studied and it was found that the reactionworks exceedingly well over a broad range of substrates. Most notably, avariety of alkynes worked in the reaction including aryl, silyl, alkyl,and ester substituted acetylenes. Note the highlighted functional groupsin the Table 4.2 below. This is highly useful and it is also noteworthythat with most other ligands, only a single type of alkyne functionswell in the reaction. StackPhos is exceptional in this regard with evenalkyl-substituted alkynes functioning quite well

TABLE 4.2

As a demonstration of the methodology and to determine the absoluteconfiguration of the products produced by the specific enantiomer ofStackPhos illustrated, three natural products were prepared. As seen inFIG. 4.1, transformation of the products 4 a, 4 i, and 4 j togalipinine, angustureine, and cuspareine was straightforward andproduced in high overall yield.

Allylic Alkylation

We have also used the ligand for palladium-catalyzed allylic alkylation,which illustrates that derivatives can be readily prepared in highenantiomeric excess. In this work, we have prepared the ligand (FIG.4.2), which illustrates the derivative can be produced.

In addition to the ligands shown thus far, we prepared other ligandssuch as those in FIG. 4.3.

Enantioselective Hydrogenation

StackPhos complexes of palladium and copper for catalysis have preparedand characterized. We have also prepared an Iridium complex:[(StackPhos)Ir(COD)]BPh4 for enantioselective hydrogenation.

Example 5

Brief Introduction:

A new strategy for increasing the barrier to rotation in biaryls isdescribed, and it is demonstrated that arene-arene interactions cancontribute to this barrier by stabilization of the chiral conformation.Using this concept, it was found that incorporation of a perfluorinatedaromatic provides an increase of ˜2 kcal/mol in the barrier to rotationabout the biaryl bond. This approach allowed for the inclusion of a5-membered heterocycle in the biaryl backbone of StackPhos, a chiralimidazole-based P,N-ligand. The preparation of this ligand as a singleenantiomer and structural analysis of palladium and copper complexesthereof are discussed in detail. These studies establish the advantagesof this class of ligands such as a unique mode of coordination inCu-complexes and a readily prepared biaryl moiety enabled by inclusionof the 5-membered heteroaromatic.

Background:

The development of new chiral ligands is essential for enantioselectivecatalysis and continues to be an important area at the forefront oforganic synthesis.¹ Of particular importance are new ligands thatintroduce fundamental changes in the chiral backbone and/or unique modesof coordination. Following the seminal reports by Brown and co-workerson QUINAP in 1993,² the development of axially chiral P,N-ligands hascontinued and modified ligands such as Quinazolinap,³ Pyphos,⁴ andPINAP⁵ have been demonstrated to perform extremely well in a variety ofasymmetric transformations.⁶ Recently, we communicated the design andsynthesis of StackPhos 5,⁷ an imidazole-based P,N ligand that exceled inthe A³-coupling reaction.⁸

The design of StackPhos was inspired by the lack of examples ofatropisomeric P,N-ligands containing 5-membered heteroaromatics in thebackbone, despite the extremely facile synthesis of these moieties andpotential for unique ligation properties. This type of ligand has beenexplored in achiral scaffolds and proved to be a promising class ofbidentate ligands. Examples of achiral benzimidazole- (6⁹ and 7¹⁰) andpyrazole-based (8¹¹) P,N-ligands have been reported and their functionin catalysis demonstrated by application to reactions such ascross-coupling.¹² Interestingly, attempts have been made to render thesebiaryl ligands chiral. P,N-ligand 9 was prepared by Brown and itsresolution attempted, but unfortunately this system is stereochemicallylabile precluding application in asymmetric catalysis.¹³ There is,however, one example of an axially chiral P,N-ligand containing a5-membered heterocycle-BIMNAP 10.¹⁴ Although 10 is known, there are noreports of its use as a ligand in a catalytic reaction. The fact that noother examples of such P,N-ligands exist is probably related to thechallenges of preparing configurationally stable biaryls with smallerring sizes.¹⁵ As a consequence, such C₁-symmetric axially chiralP,N-ligands have not been widely explored in asymmetric catalysis.

In light of this, we decided to address the issue by using afundamentally different approach to controlling the conformation inaxially chiral 5-membered heteroaromatic biaryls, namely ground statestabilization. In fact, the name StackPhos was inspired by theintramolecular π-stacking interactions that contribute to theconfigurational stability of the chiral biaryl. Herein we report thefirst studies on controlling the axial chirality of heteroaromaticbiaryls by ground state stabilization and detail how using this conceptaffects the performance of StackPhos, underscoring the practicalrelevance of this new design element.

Results and Discussion:

System Design

The chiral biaryl motif is present in a myriad of important moleculesused in areas as disparate as catalysis and medicine.^(1,16)Interestingly, the majority of the axially chiral biaryls are comprisedof 6-membered benzenoid or benzo-fused ring systems. In fact, these arethe most prevalent chiral biaryls found in both natural^(16b) andsynthetic systems.¹⁷ There are a number of reasons for this, but onevitally important element of these structures relates to how themolecules are rendered chiral. More specifically, rotation about thearyl-aryl bond is restricted by steric intrusion of ortho-substituentsand this is affected by the bond angles of the arene. It follows thatthe geometrical differences between 6- and 5-membered rings will thenalter the distances between the interacting groups of an atropisomer andtherefore affect the ease of bond rotation. As illustrated in FIG. 5.3,the larger bond angles between the substituents in a 5-membered ringwill result in a less restricted biaryl bond.¹⁵ This is perhaps acontributing factor as to why the vast majority of optically activebiaryl atropisomers are comprised of 6-membered rings and 5-memberedrings are infrequently encountered.

As these interactions are essential for atropisomerism, the principal,if not only, strategy currently taken to increase the barrier torotation in biaryls involves the incorporation of bulky orthosubstituents to increase the transition state energy. In contrast, wehypothesized that stabilizing the ground state energy would alsoincrease the barrier and this approach should be advantageous because itwould remove the requirement for sterically demanding substituents.Surprisingly, to the best of our knowledge, this simple concept has notbeen explored in the context of 5-membered heteroaromatics or biarylatropisomerism in general.

To study the feasibility of this idea, a model system comprised of threearomatic units designed to π-stack in an intramolecular fashion wasdesigned. As illustrated in FIG. 5.4, a very simplistic conformationalanalysis shows the compound in equilibrium between an achiralconformation A and the chiral conformation B. In addition to stericinteractions, the position of this equilibrium should be governed byconjugation (favoring A) and attractive arene-arene interactions(favoring B). If stabilizing arene-arene interactions would predominate,the equilibrium could be shifted to the right and favor the chiralconformation. It should also be noted that in chiral biaryls, conjugatedconformation A would be the transition state for racemization.

Preliminary Studies

To favor the chiral conformation B, the appropriate arene moieties mustbe chosen to effect the desired interaction. Perfluoroaromatics are wellknown to bind strongly to other arenes 18 and, based on theseprecedents, biaryl 14 was prepared in addition to the non-fluorinatedcontrol compound 13.20 Analysis of the methylene protons Ha and Hb by 1HNMR in each molecule should give insight into the barrier to rotationand to our delight, the methylene group of 13 appeared as broad singletwhile 14 exhibited an AB pattern (FIG. 5.5). This behavior is consistentwith restricted rotation about the biaryl bond in 14 on the 1H NMR timescale, rendering the methylene protons diastereotopic.

The barriers to rotation of 13 and 14 were then measured using thecoalescence method.²¹ FIG. 5.6 shows the ¹H NMR (expanded in themethylene peak region) for compounds 13 and 14 at different temperaturesand, as expected, the AB system observed for the methylene peak of 14gradually coalesced to a broad singlet at elevated temperatures. Uponcooling, the broad singlet observed for 13 gradually separated into anAB system. Careful analysis of the spectra provided a coalescencetemperature of 9° C. and 57° C. for 13 and 14, respectively—a remarkabledifference. The ΔG‡ for interconversion of H_(a) and H_(b) between thetwo chemical sites was calculated and the free energies of activation atthe coalescence temperatures were found to be 13.7 kcal/mol and 16.1kcal/mol for compounds 13 and 14, respectively. Comparing the calculatedenergies for bond rotation in compounds 13 and 14 gives a ΔΔG‡ of 2.4kcal/mol. By analogy to the previously described models, this energy canbe attributed to intramolecular π-stacking interactions^(21b) and thisvalue is in agreement with other π-stacking energies involvingpentafluoroaromatic moieties.¹⁸ Remarkably, although distal to thebiaryl σ-bond, simply perturbing the electronics increased therotational barrier by nearly 2.5 kcal/mol.

Further evidence of π-stacking was obtained after X-ray quality singlecrystals of 14 were obtained and analyzed (FIG. 5.7). Unfortunately,compound 13 is a viscous oil, precluding further direct comparison. Inthe solid state, the arene-arene interaction in 14 appears to occur inthe parallel-displaced arrangement.¹⁸ The two aromatic groups areparallel to each other with the benzyl arene centered over the edge ofthe naphthalene. The dihedral angle that defines the planes of the A-and B-rings is 880 and the A- and C-rings have an interplane distance of3.26 Å, which is the distance between the averaged planes of the twoslightly canted aromatics. Interestingly, this is closer than theinterplane distance of 3.4 Å found in the well-known C₆H₆ and C₆F₆co-crystal,²² likely due to constraints imparted by the C—N bond lengthin this intramolecular interaction. There are also intermolecularπ-stacking interactions between alternating naphthalene andpentafluorobenzene rings in the solid state (FIG. 5.7).

While these results provide a proof-of-principle demonstration thatarene-arene interactions can indeed function as desired, it wasimportant to understand how electronic and steric factors affect thesystem before moving from model compounds to functional molecules. Tothis end, the influence of substituents on the naphthalene were brieflystudied with the hope that the barrier could be increased to the pointwhere atropisomerism may be possible. Biaryl 15 was prepared with theintention of adding an electron-donating methoxy group to enhance theinteraction between the electron-rich naphthalene ring and anelectron-poor pentafluorobenzyl group. Based on the X-ray structure of14, substitution at 5-position of the naphthalene should directlyincrease the electron density, but surprisingly, the barrier to rotationin 15 was very similar to compound 14 (ΔG‡=16.3 kcal/mol and T_(c)=61°C.) suggesting that the pentafluorobenzyl moiety dominates theinteraction regardless of the nature of the naphthalene ring (FIG. 5.8).Gung and co-workers observed the same trend when studying π-stackinginteractions involving strongly electron deficient aromatic rings.²³

Positioning a methoxy group ortho to the biaryl bond presented a veryhigh barrier to rotation in 16, even in the absence of thepentafluorophenyl group. The ¹H NMR spectrum of this compound inC2D2Cl4²⁴ exhibited an AB system that did not coalesce at 120° C. andthe barrier could not be determined.²⁵ The isoquinoline derivative 17,on the other hand, exhibited a very low barrier to rotation that alsocould not be determined by the coalescence method.²⁵ These resultsclearly demonstrate that sterics are also important, with groups assmall as hydrogen significantly contributing to the barrier to rotation.

Although 17 exhibited an extremely low barrier, the indole 18 wasprepared for comparison to 14 (FIG. 5.9). Surprisingly, the coalescencetemperature and the barrier to rotation increased considerably bychanging the B-ring to an indole (from 16.1 to 17.3 kcal/mol). Thesedata show that the nature of the heterocycle affects the barrier torotation of these compounds and suggests that a “buttressing effect”might be playing a role.²⁶ To further investigate this rationale, a5-substituted pyrrole that maintained the n-system but altered thesterics was prepared (FIG. 5.9). As expected, the barrier to rotationincreased to 16.5 kcal/mol. While this change is not of the samemagnitude as changing to the indole, it demonstrated that substitutionat this position could prove to be important for increasing the barrier.

Further modifications were made to probe the influence of substituentson the benzyl group. As can be seen in FIG. 5.9, while the perfluoroderivative 18 had a substantially higher barrier than the des-fluoroanalog 20, no significant difference was observed between any of theother compounds, including the mono-fluoro derivative 21. These datawere somewhat unexpected, underscoring the complexity of the system.

The information gleaned from the model studies was quite instructive andcould be used to increase the barrier in functional molecules asfollows. Firstly, the highest barrier to rotation observed was 17.3kcal/mol. It is important to note that, by definition,²⁷ an atropisomerhas a barrier of at least ˜22 kcal/mol at room temperature, so acombination of sterics and electronics will likely be necessary toincrease the barrier to at least this level and, for all practicalpurposes, higher. When appending a group to induce stabilizingarene-arene interactions, the pentafluorophenyl benzyl group is a goodchoice because it obviates the need for changing the electronics of thenaphthalene ring by substitution. These studies showed that by includingthis moiety, an increase of at least 2 kcal/mol can be achieved.Finally, inclusion of a group ortho to the benzyl group on theheterocycle, while removed from the arene-arene interaction, canactually increase the barrier to rotation (as in 18 and 19). Theseenergetic contributions can be crucial when developing new ligands forasymmetric catalysis. Indeed, our recent report demonstrated that anextra 2.2 kcal/mol of stabilization was essential vide infra.⁷

Ligand Design

StackPhos (5, FIG. 5.1), a 5-membered heterocyclic biaryl, was designedto include the important structural elements identified above toincrease the barrier to rotation, rendering it chiral. With the goal ofproducing an atropisomeric P,N-ligand, it was decided that aphosphine-substituted naphthalene moiety and a 5-membered heterocyclecontaining a basic nitrogen would be incorporated for coordination. Thenitrogen heterocycle would be an imidazole to permit both coordinationand facile incorporation of a pentafluorophenyl group for π-stacking.Furthermore, this group was predicted to obviate the need forsubstitution of the naphthalene ring as described above, allowing it toretain the same elements as successful ligands such as BINAP, QUINAP,etc. The choice of imidazole also was thought to be advantageous becausea substituent at the 5-position could be introduced to enforce abuttressing effect and raise the barrier to rotation. Other potentiallyattractive salient features were the ability to include substituents inthe 4-position to protrude into the space defining the ligand's chiralbinding pocket and a facile heterocycle synthesis by condensation. Asdescribed previously, preparation of racemic StackPhos was achieved fromreadily available starting materials in 33% overall yield.⁷ Evidencethat the design elements established by the studies described aboveinfluenced the barrier to rotation was obtained by measuringΔΔG‡_(75° C.)=2.2 kcal/mol between StackPhos and the des-fluoro analogas well as X-ray crystallography.⁷ The experimental barrier to rotationof StackPhos was observed to be 28.4 kcal/mol,⁷ and hence it isatropisomeric. For catalysis, a single enantiomer was needed and thisproved to be extremely challenging; however, the design of the ligandproved to be quite uniquely advantageous and the ligand was prepared asa single enantiomer through a novel deracemization process, which isdescribed in full detail below.

Deracemization of the P,N-Ligand

The resolution of axially chiral P,N-ligands usually requires the use ofa chiral palladium complex dimer such as 24 (for structure, see FIG.5.11).^(2,28) Upon complexation of the P,N-ligand with 24, a 1:1 mixtureof diastereomers is formed and separated by fractional crystallization.After decomplexation of the chiral palladium moiety, a single enantiomerof the ligand is obtained. This method works exceedingly well over awide range of axially chiral P,N-ligands.²⁹ To this end, we performed anexperiment at ambient temperature in acetone in which the racemic ligandrac-5 and the palladium dimer 24 were mixed in the presence of potassiumhexafluorophosphate, and a 1:1 mixture of diastereomers 25 and 26 wasobserved (FIG. 5.10). This equimolar mixture was isolated and fractionalcrystallization was attempted, however, after extensively screeningconditions this method proved to be unsuccessful. Interestingly, duringattempts to optimize this separation process, it was realized that theratio of diastereomers would slightly change and this was seemingly notdue to a fractional crystallization. This observation was made whenconditions at higher temperatures were employed and this suggested thatit may be possible to interconvert the two diastereomers. Brown'sindole-based P,N-ligand 9 (FIG. 5.2) readily gives a single diastereomerwhen treated with chiral palladium complex 24 at room temperature,¹³ butQUINAP complexes do not interconvert even at elevated temperatures.²⁸Based on this data, we were encouraged to heat the diastereomericmixture to possibly equilibrate the system to a single diastereomer,although this would rely on a significant energy difference between 25and 26.

To probe this, a 1:1 mixture of diastereomers 25/26 in acetone washeated at 60° C. for 24 h. To our delight, a single diastereomer wasobserved as judged by ¹H NMR. To evaluate the practicality of thisprocess, the experiment was performed on a larger scale by mixingracemic phosphine 5 with palladium complex 24 and KPF₆ in acetone. Afterrefluxing the mixture for 24 hours the solution was filtered off, thesolvent removed, and a single diastereomer was observed in the NMR ofthe crude reaction mixture. A single recrystallization gives the purediastereomer 25 in 81% yield (FIG. 5.10). As both enantiomers of 24 areavailable, this process allows the rapid conversion of racemic ligand toa single enantiomer of 25, without the classical problem of losing 50%of the material during a kinetic resolution process.

Interestingly, this equilibration process was fairly demanding andrequired that the chiral amine resolving agent 24 contained thenaphthalene substituent. Attempts were made to utilize the phenylsubstituted palladium complex 27 but resulted in only a 1:1 mixture ofdiastereomers under the equilibrating conditions described above (FIG.5.11). Brown also observed the requirement for the naphthalene whilestudying palladium complexes formed from QUINAP.^(2,30) Resolution ofQUINAP employing complex 24 was achieved with success whereas 27 did notgenerate separable palladium complexes. It's believed that the fusedbenzene ring changes the conformational requirements, and consequently,a greater difference in energy for the pair of diastereomers is observedmaking the fractional crystallization more facile using thenaphthalene-based system.³⁰ With complex 28, the 5-membered palladacyclein the auxiliary must allow the benzylic methyl group more degrees offreedom, diminishing the energy difference between the diastereomers. In25/26, the benzylic methyl groups likely have a greater conformationalconstraint through interaction with the peri H of the naphthaleneresulting in a larger energy difference between diastereomers.

As the deracemization phenomenon is unique to this imidazole-basedP,N-ligand system, it seemed prudent to gain a more thoroughunderstanding of the important factors involved. The structuraldifferences responsible for the difference in stability between the twodiastereomers 25 and 26 were probed using X-ray crystallography whensingle crystals of an equimolar mixture of 25 and 26 were obtained andthe structure solved. The X-ray structure of the crystals revealed a 1:1packing of the two diastereomers (FIG. 5.12) and allowed for aconformational analysis to provide insight into the crucial stericinteractions responsible for the difference in energy. For clarity, thecrystal structures of each diastereomer are depicted separately in FIG.5.13. The most striking difference between the two structures is theconformation of the 5-membered palladacycle. In the more stable isomer25 it has adopted an “envelope” conformation whereas it is “flattened”in 26. This planarity likely introduces strain to the system, raisingits energy and thereby favoring diastereomer 25 under equilibratingconditions.

Analysis of StackPhos and complexes thereof With a good source of 25 inhand, the overall goal was to obtain StackPhos 5 in high ee for use as aligand for asymmetric catalysis; however, the structural features ofligand metal complexes such as 25 are also of interest as they mayprovide later insight into catalytic reactions.³¹ To this end, asdescribed above, 25 was isolated as a single diastereomer andcrystallized to obtain a separate X-ray structure in the absence of 26(FIG. 5.14). Interestingly, in the solid state, the pentafluorobenzylgroup of 25 is pointed away from the naphthalene ring instead ofinteracting with this moiety through the predicted arene-arene observedin the crystal structure of the free ligand StackPhos 5.⁷ Instead, thefluorinated aromatic ring is x-stacking with the phenyl group in the5-position of the imidazole. A possible explanation for this is that thesmall dihedral angle observed in the biaryl moiety (54.3°) is requiredto bind to the metal in a bidentate fashion. Consequently, toaccommodate this the pentafluorophenyl must rotate away from thenaphthalene moiety to avoid repulsive steric interactions. In otherwords, upon complex formation, bond rotation decreases the dihedralangle preventing the π-stacking interaction observed in the freephosphine.⁷ In the case of the free StackPhos, a much larger dihedralangle is observed (84.9°) allowing for what must be a more highlystabilizing arene-arene interaction with the naphthalene.⁷

The motivation for this work was to provide a new type of heterocyclicP,N-ligand that moves from a 6-membered aryl moiety to a 5-memberedheteroaromatic. At the outset we thought that this would be advantageousfor a number of reasons related to ease of synthesis and tuning of theligand, but the shift to a 5-membered ring would likely also haveprofound effects on the structures of complexes of StackPhos andpresumably also catalysts thereof. For comparison to a 6-memberedheterocyclic P,N-ligand, the X-ray crystal structure of palladiumcomplex 25 was analyzed and compared to the analogous QUINAP complex29.³⁰ The structures are displayed in FIG. 5.10 and have the samestereochemistry with respect to both the atropisomer and the resolvingagent. The dihedral angles θ and bite angles ϕ are listed for bothstructures. Although the bite angle ϕ is slightly smaller in 25, thedihedral angle θ is significantly smaller (>10° difference) probably dueto the smaller 5-membered imidazole ring. The chiral environment aroundthe metal center in both P,N-ligands are shown with space fillingstructures. The selected views illustrate that a significant differencein the steric profile of the complexes is present, which both originatesfrom and is most pronounced in the region about the imidazole moiety.Interestingly, the phenyl group at the 4-position of this 5-memberedheterocycle helps to generate a bulky chiral environment reminiscent ofBINAP.³² Decomplexation and release of a single enantiomer of StackPhos

With a good synthesis of a single diastereomer of 25 in hand, whatremained was to isolate free StackPhos by decomplexation. With thedemonstration of the stereochemical lability of 25, albeit at elevatedtemperatures, isolating StackPhos without erosion of the ee was ofconcern with the potential for this problem to originate either byepimerization or racemization at the complex or free ligand stagesrespectively. While most axially chiral P,N-ligands have a high barrierthat prevents racemization,^(28,33) for StackPhos this was initially anunknown and a careful analysis of the enantiomeric excess of free ligandwould be needed after decomplexation. Unfortunately, all attempts toanalyze the ee of rac-5 by HPLC using a chiral stationary phase wereunsuccessful; however, after oxidation of rac-5 to the correspondingphosphine oxide a baseline separation was observed.^(34,35)

To isolate free StackPhos, decomplexation was effected by reaction ofent-25 with one equivalent of dppe.³⁶ This enantiomer of 25 was utilizedso that direct comparison to known copper complexes could be made videinfra. The initial experiments were conducted at ambient temperature indichloromethane and 5 was recovered in high yield after columnchromatography (Table 5.1, Entry 1). Surprisingly, the enantiomericexcess of StackPhos 5 ranged from 88 to 92% with these conditions andclearly this procedure needed improvement.

TABLE 5.1 Optimization of the decomplexation reaction.^(a)

Entry Temp (° C.) yield (%) ee (%) 1 22 90-100 88-92 2 0 95 90 3 −78 noreaction — 4 −78 to 0 97 98 ^(a)The ee was determined by HPLC afteroxidation to the phosphine oxide.

At this stage is was unclear whether the low ee material was a result ofhaving small amounts of the minor diasteromer (ent-26) present in thestarting complex, if ent-26 was being formed under the conditions, oreven if StackPhos may be epimerizing to a small extent. Despite thisuncertainty, reducing the temperature could potentially improve theoptical purity if the problem was a small loss of ee during thedecomplexation process. Interestingly, at 0° C., no improvement wasobserved in terms of yield or enantiomeric excess and at −78° C. therewas no reaction due to low solubility of dppe in CH₂Cl₂ using a solidaddition protocol (Table 5.1, entries 2 and 3). Fortunately, it wasfound that adding solid dppe to a solution of 25 at −78° C. and warmingthe mixture to 0° C. would release the ligand in 98% enantiomeric excessafter one hour. The absolute stereochemistry of StackPhos was determinedby X-ray crystallography of palladium complex 25 with known absoluteconfiguration.³⁶ StackPhos as a ligand for enantioselective catalysis

In our previous communication, it was shown that StackPhos was anexcellent ligand for the enantioselective A³-coupling reaction,furnishing the propargylamine products 32 in high yields andenantioselectivities over a broad range of substrates, including alkyland aryl aldehydes (FIG. 5.15).⁷ With StackPhos, the catalyst formed insitu exhibited a much greater reactivity and allowed for the use ofelectron deficient aldehydes and overcoming the limitations in scopeassociated with QUINAP, the benchmark ligand for this reaction.³⁷ Sincethe reactions were faster and could be performed at 0° C., thisimprovement in reactivity prompted us to study a 5.CuBr complex to gleaninsight into the factors responsible.

Fortunately, using enantiomerically pure StackPhos and CuBr, X-rayquality single crystals could be grown and the structure was solved.Interestingly, this analysis revealed the structure to be a dimericcomplex [CuBr{(S)-5}]₂ 34 which greatly differed from that of theQUINAP.CuBr complex 33.^(38,39) With StackPhos, the two P,N-ligandspresent in 34 are clearly different with one coordinating in a bidentatefashion and the other monodentate. Interestingly, the bidentateP,N-ligand is coordinated to two different copper atoms that are bridgedwith a bromine atom, forming an eight-membered ring (FIGS.5.16A-5.16C).⁴⁰ The formation of this large ring allows for a dihedralangle of 89.9° in the biaryl moiety. Consequently, the intramolecularπ-stacking interaction between the pentafluorobenzyl moiety andnaphthalene is feasible because this type of coordination does not forceunfavorable steric interaction between the two arene moieties.Interestingly, the monodentate P,N-ligand is also stacking and thedihedral angle is 78.4°.

Although this structural information comes from the solid state, itimplies that formation of a more traditional bidentate complex betweenStackPhos and CuBr may be unfavorable. In solution, by analogy to QUINAPcomplex 33, the analogous structure 35 was hypothesized to potentiallyexplain greater reactivity. If StackPhos is monodenatate, this mayprovide for a more accessible metal center with the solid statestructure 34 being produced by coordination of an imidazole nitrogen of35 to copper and displacement of a bromine atom as shown below. Bychanging the 6-membered isoquinoline heterocycle to the 5-memberedimidazole present in StackPhos, the mode of coordination is greatlyinfluenced. In this setting, it provides an enhancement in reaction rateproviding the products in high ee. This demonstrates that theincorporation of 5-membered heterocycles into the chiral biaryl backbonecan be enormously beneficial and provide enhancements to catalysis thatare inaccessible by maintaining the 6-membered arene biaryl motif.

In summary, the studies described here detail a new strategy to increasethe barrier to rotation in biaryl atropisomers. Model studiesdemonstrate that by simply including aromatics that form stabilizingarene-arene interactions, the barrier to rotation can be increased by ˜2kcal/mol. Incorporation of this simple design element should beapplicable to a wide variety of biaryls, enabling an increase in barrierwithout the need to increase steric demand about the biaryl bond. Thepresent study describes how utilizing this concept enabled theincorporation of an imidazole, a 5-membered heteroaromatic arene, intoStackPhos, a new chiral biaryl P,N-ligand. Interestingly, this ligandπ-stacks in the originally anticipated mode in the free ligand, but theinteraction is replaced by a different arene-arene interaction uponforming palladium complex 25. This is extremely fortuitous as it thenpermits a unique deracemization process novel amongst this class ofligands. After decomplexation, the stabilizing arene-arene interactionbetween the pentafluorobenzyl and naphthyl moieties is reformed toprovide StackPhos as a configurationally stable ligand.

Complexes of StackPhos with palladium and copper were prepared andstructural comparison is made to complexes of the highly successfulligand QUINAP to probe the differences between 5- and 6-memberedheteroaromatics. Interestingly, these data suggest that the imidazoleplays an important role in defining the chiral space through itssubstituents and by changing the dihedral angle required for bidentatecoordination. These influences appear to be extremely important andsignificantly different than known ligands.

From a broader perspective, this previously unexplored class of ligandsshould provide a unique, highly tunable scaffold for the development ofnew chiral ligands and catalysts for enantioselective reactions. Theexpansion of this new design element to the synthesis of additional newligands and catalysts has emerged in our group in combination with theinvestigation of new enantioselective reactions enabled by theseligands.

REFERENCES

-   1. (a) Comprehensive Asymmetric Catalysis, Vol. 1-3 (Eds.: E. N.    Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999. (b)    Qi-Lin Zhou (Ed.), Privileged Chiral Ligands and Catalysts,    Wiley-VCH, Weinheim, 2011.-   2. Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry    1993, 4, 743-756.-   3. (a) McCarthy, M.; Goddard, R.; Guiry, P. J. Tetrahedron:    Asymmetry 1999, 10, 2797-2807. (b) Connolly, D. J.; Lacey, P. M.;    McCarthy, M.; Saunders, C. P.; Carroll, A.-M.; Goddard, R.;    Guiry, P. J. J. Org. Chem. 2004, 69, 6572.-   4. Kwong, F. Y.; Chan, A. S. C.; Chan, K. S. Tetrahedron 2000, 56,    8893-8899.-   5. Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;    Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971-5973.-   6. Fernández, E.; Guiry, P J.; Connole, K. P. T.; Brown, J. M. J.    Org. Chem. 2014, 79, 5391-5400.-   7. Cardoso, F. S. P.; Abboud, K. A.; Aponick, A. J. Am. Chem. Soc.,    2013, 135, 14548-14551.-   8. (a) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V.    Chem. Soc. Rev. 2012, 41, 3790-3807. (b) Yoo, W.-J.; L. Zhao, L.;    Li, C.-J. Aldrichim. Acta 2011, 44, 43-51.-   9. Chung, K. H.; So, C. M.; Wong, S. M.; Luk, C. H.; Zhou, Z.;    Lau, C. P.; Kwong, F. Y. Chem. Commun. 2012, 48, 1967-1969.-   10. Song, B.; Knauber, T.; Gooßen, L. J. Angew. Chem., Int. Ed.    2013, 52, 2954-2958.-   11. Singer, R. A.; Caron, S.; McDermott, R. E.; Arpin, P.; Do, N. M.    Synthesis 2003,11, 1727-1731.-   12. (a) Fromm, A.; van Wüllen, C.; Hackenberger, D.; Gooßen, L. J.    Am. Chem. Soc., 2014, 136, 10007-10023. (b) Wong, S. M.; So, C. M.;    Chung, K. H.; Lau, C. P.; Kwong, F. Y. Eur. J. Org. Chem. 2012,    4172-4177.-   13. Claridge, T. D. W.; Long, J. M.; Brown, J. M.; Hibbs, D.;    Hursthouse, M. B. Tetrahedron 1997, 53, 4035-4050.-   14. Figge, A., Altenbach, H. J., Brauerb, D. J., Tielmannc, P.    Tetrahedron: Asymmetry 2002, 13, 137-144.-   15. Alkorta, I.; Elguero, J.; Roussel, C.; Vanthuyne, N.; Piras, P.    Atropisomerism and Axial Chirality in Heteroaromatic Compounds. Adv.    Heterocycl. Chem. 2012, 105, 1-188.-   16. (a) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPante S. R.    Angew. Chem. Int. Ed. 2009, 48, 6398. (b) Bringmann, G.; Gulder, T.;    Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111, 563-639.-   17. Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M.    J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44,    5384-5427.-   18. (a) Meyer, E. A., Castellano, R. K.; Diederich, F. Angew. Chem.,    Int. Ed 2003, 42, 1210-1250. (b) Salonen, L. M., Ellermann, M.,    Diederich, F. Angew. Chem., Int. Ed. 2011, 50, 4808-4842.-   19. Intentionally skipped-   20. Ohkubo, M.; Hayashi, D.; Oikawa, D.; Fukuhara, K.; Okamoto, S.;    Sato, F. Tetrahedron Lett. 2006, 47, 6209-6212.-   21. (a) O. Sutherland, Annu. Rep. NMR Spectrosc., 1971, 4, 71. (b)    Mati, I. K.; Cockroft, S. L. Chem. Soc. Rev. 2010, 39, 4195-4205.-   22. (a) Patrick, R.; Prosser, G. S. Nature 1960, 187, 1021. (b)    Williams, J. H.; Cockcroft, J. K.; Fitch, A. N. Angew. Chem., Int.    Ed. Engl. 1992, 31, 1655-1657.-   23. Gung, B. W.; Xue, X. W.; Zou, Y. J. Org. Chem. 2007, 72,    2469-2475.-   24. For a matter of comparison, the barrier to rotation of 20 in    C₂D₂Cl₄ and CDCl₃ were measured and it was observed that they are    comparable when using these solvents.-   25. The practical range for barriers determined using the    coalescence method is defined by the temperature limitations of the    NMR probe.-   26. (a) Bott, G.; Field, L.-D.; Sternhell, S. J. Am. Chem. Soc.    1980, 102, 5618-5626. (b) Rieger, M.; Westheimer, F. H. J. Am. Chem.    Soc. 1950, 72, 19-28.-   27. Oki, M. Top. Stereochem. 1983, 14, 1-76.-   28. Lim, C. W.; Tissot, O.; Mattison, A.; Hooper, M. W.; Brown, J.    M.; Cowley, A. R; Hulmes, D I.; Blacker, A. J. Org. Process Res.    Dev. 2003, 7, 379-384.-   29. Li, Y.-M.; Kwong, F.-Y.; Yu, W.-Y.; Chan, A. S. C. Coord. Chem.    Rev. 2007, 251, 2119-2144.-   30. Alcock, N. W.; Hulmes, D. I.; Brown, J. M. J. Chem. Soc., Chem.    Commun. 1995, 395-397.-   31. (a) Carroll, M. P.; Guiry, P. J.; Brown, J. M. Org. Biomol.    Chem. 2013, 11, 4591-4601. (b) Birkholz, M.-N.; Freixa, Z.; van    Leeuwen, P. W. N. M. Chem. Soc. Rev. 2009, 38, 1099-1118.-   32. Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345-350.-   33. (a) Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346,    497-537. (b) Carroll, M. P.; Guiry, P. J. Chem. Soc. Rev. 2014, 43,    819.-   34. For separation of racemic phosphine oxide in a P,N-ligand see:    Kwong, F. Y.; Yang, Q.; Mak, T. C. W.; Chan, A. S. C.;    Chan, K. S. J. Org. Chem. 2002, 67, 2769-2777.-   35. This oxidation was performed in quantitative yield using    hydrogen peroxide in dichloromethane and was performed in an    analytical fashion. For full details, see ref 7.-   36. The palladium complex ent-25 was prepared analogously to 25 as    shown in Scheme 3.-   37. (a) Gommermann, N.; Koradin, C.; Polbom, K.; Knochel, P. Angew.    Chem. Int. Ed. 2003, 42, 5763-5766. (b) Gommermann, N.; Knochel, P.    Chem. Eur. J. 2006, 12, 4380-4392.-   38. Koradin, C.; Gommermann, N.; Polbom, K.; Knochel, P. Chem.    Eur. J. 2003, 9, 2797-2811.-   39. For a similar complex, Quinazolinap-CuCl, see: Fleming, W. J.;    Muller-Bunz, H.; Lillo, V.; Fernandez, E.; Guiry, P. J. Org. Biomol.    Chem. 2009, 7, 2520-2524.-   40. For an example of a bidentate ligand bridging two coppers, see:    Shishkov, I. V.; Rominger, F.; Hofmann, P. Dalton Trans. 2009,    1428-1435.

It should be noted that ratios, concentrations, amounts, and othernumerical data may be expressed herein in a range format. It is to beunderstood that such a range format is used for convenience and brevity,and thus, should be interpreted in a flexible manner to include not onlythe numerical values explicitly recited as the limits of the range, butalso to include all the individual numerical values or sub-rangesencompassed within that range as if each numerical value and sub-rangeis explicitly recited. To illustrate, a concentration range of “about0.1% to about 5%” should be interpreted to include not only theexplicitly recited concentration of about 0.1 wt % to about 5 wt %, butalso include individual concentrations (e.g., 1%, 2%, 3%, and 4%) andthe sub-ranges (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within theindicated range. In an embodiment, the term “about” can includetraditional rounding according to the measurement technique and the typeof numerical value. In addition, the phrase “about ‘x’ to ‘y’” includes“about ‘x’ to about ‘y’”.

Many variations and modifications may be made to the above-describedembodiments. All such modifications and variations are intended to beincluded herein within the scope of this disclosure and protected by thefollowing claims.

The invention claimed is:
 1. A method of making a biaryl compound,comprising:

wherein the biaryl product has the following structure:

wherein each of the R₅ groups is independently selected from the groupconsisting of: hydrogen, a halogen group, a 3 to 10 carbon atom cyclicalkyl group, a 1 to 20 carbon atom linear alkyl group, an aryl group, a—OR group, a —SR group, a —SiR₍₃₎ group, a NR₍₂₎ cyclic group, and aNR₍₂₎ linear group, wherein each R is independently selected from thegroup consisting of: hydrogen, a 3 to 10 carbon atom cyclic alkyl group,a 1 to 20 carbon atom linear alkyl group, and an aryl group, wherein nis 1 to 5, wherein X is C or S, wherein each R₆ and R₇ group isindependently selected from the group consisting of: hydrogen, a 3 to 10carbon atom cyclic alkyl group, a 1 to 20 carbon atom linear alkylgroup, and an aryl group, wherein X1 is Cl, Br, or I and wherein Y is C,N, O, or S, wherein R₁ group and R₂ group are independently selectedfrom the group consisting of: hydrogen, a halogen group, a 3 to 10carbon atom cyclic alkyl group, a 1 to 20 carbon atom linear alkylgroup, an aryl group, a —OR group, a —SR group, a —SiR₍₃₎ group, a NR₍₂₎cyclic, and NR₍₂₎ linear group, wherein each of the R₄ groups isindependently selected from the group consisting of: hydrogen, a halogengroup, a 3 to 10 carbon atom cyclic alkyl group, a 1 to 20 carbon atomlinear alkyl group, an aryl group, a —OR group, a —SR group, a —SiR₍₃₎group, a NR₍₂₎ cyclic group, and a NR₍₂₎ linear group, wherein m is 1 to5, wherein each of the R₃ groups is independently selected from:hydrogen, a 3 to 10 carbon atom cyclic alkyl group, a 1 to 20 carbonatom linear alkyl group, an alkoxide, a phenoxide, an aryl group, and anamine, wherein DME is dimethoxyethan, TBS is tert-butyldimethylsilylgroup, Tf is triflate group, DMAP is 4-dimethylaminopyridine.
 2. Amethod of forming a compound, comprising:

wherein F₅ represents a F attached to each of the 5 carbons of the ring,wherein TBS is tert-butyldimethylsilyl group.
 3. A method of forming acompound, comprising:

wherein F₅ represents a F attached to each of the 5 carbons of the ring.4. A method of using a biaryl compound, comprising: using a biarylcompound as a catalyst in a reaction selected from one of the following:an enantioselective transformation, an alkyne addition asymmetricallylic alkylation, and an addition to an aliphatic or an aromaticaldehyde, wherein the biaryl compound has the following structure:

wherein each of the R₅ groups is independently selected from: hydrogen,a halogen group, a cyclic or linear, alkyl group, an aryl group, a —ORgroup, a —SR group, a —SiR₍₃₎ group, a NR₍₂₎ cyclic or linear group,wherein each R is independently selected from: hydrogen, a cyclic orlinear, alkyl group, or an aryl group, wherein n is 1 to 5, wherein X isC or S, wherein each R₆ and R₇ group is independently selected from:hydrogen, a cyclic or linear, alkyl group, an aryl group, wherein R₁group and R₂ group are independently selected from: hydrogen, a halogengroup, a cyclic or linear, alkyl group, an aryl group, a —OR group, a—SR group, a —SiR₍₃₎ group, a NR₍₂₎ cyclic or linear group, wherein eachof the R₄ groups is independently selected from: hydrogen, a halogengroup, a cyclic or linear, alkyl group, an aryl group, a —OR group, a—SR group, a —SiR₍₃₎ group, a NR₍₂₎ cyclic or linear group, wherein m is1 to 5, wherein each of the R₃ groups is independently selected from:hydrogen, a cyclic or linear, alkyl group, an alkoxide, a phenoxide, anaryl group, or a substituted amine.
 5. A method comprising:

wherein compound 7 is

wherein F₅ represents a F attached to each of the 5 carbons of the ring,and wherein R is selected from SiMe₃ and Ph.
 6. A method, comprising:

wherein compound rac-7 is

wherein F₅ represents a F attached to each of the 5 carbons of the ring,wherein TMS is a trimethylsilyl group.
 7. A method, comprising:

wherein compound 7 is

wherein F₅ represents a F attached to each of the 5 carbons of the ring,wherein R is selected from the group consisting of H, OMe, and CF₃.
 8. Amethod comprising:

wherein aldehyde 1 is

and product 1 is

or wherein aldehyde 2 is

and product 2 is

or wherein aldehyde 3 is

and product 3 is

or wherein aldehyde 4 is

and product 4 is

or wherein aldehyde 5 is

and product 5 is

or wherein aldehyde 6 is

and product 6 is

or wherein aldehyde 7 is

and product 7 is

or wherein aldehyde 8 is

and product 8 is

and wherein compound 7 is

wherein F₅ represents a F attached to each of the 5 carbons of the ring.